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gen_40ee77306980dbbb51726e2a783c5a95 | Preventing EGFR activation in glioblastomas | The Brain Tumour Charity | Erasmus MC | HRCS22_14481 | Not available | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_4fa88b5eca2f75669a656bd402cddb94 | Extrachromosomal DNA maintenance mechanisms and targeting in glioblastoma | The Brain Tumour Charity | Jackson Laboratory | HRCS22_14497 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public
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gen_d7178a0d8c26b3c254d87f49f6f90bab | Intra-host genetic diversity of Hepatitis B virus among mother-infant pairs in Botswana | Wellcome Trust | Botswana Harvard AIDS Institute Partnership | HRCS22_14505 | Perinatal transmission is a major route of hepatitis B virus (HBV) transmission in countries with high prevalence rates. 80-90% of HBV infections acquired in the first year of life result in a chronic infection. HBV e antigen positivity and/or HBV viral loads, increases risk of perinatal transmission. HBV vaccination has reduced HBV incidence in infants in some parts of the world. However, the African region has the highest HBV incidence of 2.34% in children under 5 years of age. The World Health Organization plans to eliminate HBV by 2030, by decreasing the HBV prevalence to less than 0.1% in children who are 5 years of age. This project aims to investigate viral transmission dynamics and intra-host evolution of HBV in mother-infant pairs in Botswana. We will screen for HBV infections in 450 mother-infant pairs from a previous study conducted in 2016–2021. We will further determine HBV diversity in the HBV positive mother-infant pairs using next generation sequencing and novel bioinformatics pipelines. This study will enhance understanding of HBV evolution and inform development of vaccines which are effective against vaccine escape mutations and including routine HBV screening as part of antenatal care. Understanding HBV evolution gives insights in virus-host interactions. | 2.2 Factors relating to physical environment | 6project_grants_public
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gen_bf88dd207bf0c426a2c1a2fd38e15ecf | Field evaluation and implementation of rapid diagnostic test for the diagnosis of syphilis in people living with HIV/AIDS. | Wellcome Trust | Centro Internacional de Entrenamiento e Investigaciones Medicas | HRCS22_14508 | Syphilis remains as a public health concern despite effective treatment, especially in people living with HIV/AIDS (PLWHA) since central nervous system and ocular involvement is more frequent. Syphilis screening is an integral component of HIV care, but its coverage is suboptimal and current diagnostic approach in Colombia relies on at least two subsequent laboratory tests, requiring several visits to the clinic, hindering timely treatment. Rapid diagnostic tests (RDT) for syphilis do not require laboratory facilities and can be performed at the point of care, shortening the time to treatment, as demonstrated in antenatal care programs. Even though, diagnostic performance of RDT is good enough for their implementation in antenatal care and sexually transmitted infections clinics, they have not been sufficiently studied in PLWHA. Therefore, this project intent to evaluate the clinical utility of RDT, the first phase is a cross-sectional design to evaluate the diagnostic performance of RDT for syphilis in this population, and the second phase corresponds to a before and after design, to evaluate the impact of the implementation of this tests on the care of HIV patients with syphilis. | 4.1 Discovery and preclinical testing of markers and technologies | 6project_grants_public
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gen_920029dfd4fc8be678c583cbbe050c5f | Investigations into how Anopheles-specific flaviviruses affect arbovirus and Plasmodium transmission | Wellcome Trust | International Centre of Insect Physiology and Ecology | HRCS22_14509 | Despite the vast diversity of arboviruses endemic in East Africa, most research efforts have focused on just a few key viral pathogens. Additionally, estimates of arbovirus diversity in the tropics are likely to be underestimated, especially in Anopheles spp. Many arboviruses are vertically transmitted in mosquitoes, as are recently identified clades of insect-specific flaviviruses (ISFVs). Some ISFVs can either inhibit or enhance replication of other arboviruses in mosquitoes and thus impact both horizontal and vertical transmission of arboviruses. However, whether Anopheles-specific flaviviruses affect arbovirus or malaria (Plasmodium) transmission remains unknown. This study will 1) culture these viruses in Anopheles cell lines and examine their effect on secondary arbovirus inoculations; 2) secondarily infect Anopheles gambiae with arboviruses (Wesselsbron , Semliki Forest, and o’nyong-nyong viruses) after infection with ANFV; 3) characterise vector and viral gene expression responses to primary AnFV infections and with arbovirus infections using transcriptome sequencing; and 4) investigate the effects of AnFVs on Plasmodium transmission. The results from this study will inform on the potential utility of vertically transmitted AnFVs for blocking the transmission of arboviruses and or malaria parasites in Anopheles mosquitoes. | 2.2 Factors relating to physical environment | 6project_grants_public
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gen_e710e8d5dfe740f9734b2926f077dc62 | Investigating mechanisms for disseminating the Plasmodium-inhibiting Microsporidia MB symbiont in Anopheles arabiensis | Wellcome Trust | International Centre of Insect Physiology and Ecology | HRCS22_14510 | There has been recent research interest in the prospect of modifying mosquito vectors to make them resistant to Plasmodium infections. One method of modifying mosquitoes involves symbiotic microbes which protect their hosts from infection and are known to persist across multiple generations (transmitted from mother to offspring). Our team has recently isolated a novel fungal symbiont (microsporidia) which occurs naturally in the Anopheles mosquitoes. The symbiont confers mosquitoes a protective phenotype against malaria, both in the wild and under controlled laboratory settings. This finding offers a potential avenue to develop a novel malaria control strategy. To ensure the symbiont is useful as part of a control strategy, we will need to find a way to increase the infection rate in wild mosquitoes (5-10% of Anopheles mosquitoes harbor this fungal symbiont). The proposed research will investigate two possible methods to increase infections rates; a) dissemination of fungal symbiont spores b) Using a pathogenic fungus to kill uninfected mosquitoes (hence increasing the proportion of infected ones). The outcome of this research will be a better insight into methods to practically modify a mosquito population to harbor an enduring transmission blocking microbe. | 2.2 Factors relating to physical environment | 6project_grants_public
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gen_318f779c7699239d31d27356a667c86f | Using light to treat fungal infections: photodynamic therapy as an alternative technology to overcome candidiasis | Wellcome Trust | FUNDAÇÃO DE APOIO AO DESENVOLVIMENTO DA UNIVERSIDADE FEDERAL DE PERNAMBUCO (FADE) | HRCS22_14513 | Candidiasis is the 7th most common bloodstream infection in Brazilian hospitalized patients and represents 74% of serious fungal infections in Brazil. Superficial forms of candidiasis can lead to disfiguration, disability, and can potentially become systemic and lethal. There is a limited number of antifungal drugs available and the unpaired increase of antifungal resistance highlights the urge to develop alternative technologies to treat fungal infections. Photodynamic inactivation(PDI) has been suggested as a promising antimicrobial technology, and no microbial resistance has been described against it. PDI uses light to produce reactive oxygen species and destroy pathogenic cells. Our group has been investigating the effect of PDI on Leishmania spp. and yeast-forms of Candida albicans using zinc porphyrins (ZnP). The organization of Candida in biofilms grants it a higher resistance to antifungals, including PDI. The association of PDI with metallic nanoparticles (ZnP-NP) has been suggested to improve the photodynamic efficiency in biofilms. We propose to develop a protocol to apply ZnP and ZnP-NP PDI for planktonic cells and biofilms of C. albicans and C. glabrata. The establishment of this technology to treat candidiasis will decrease the exposure of patients to antifungal drugs, preventing the emergence of new resistant Candida strains. | 2.2 Factors relating to physical environment | 6project_grants_public
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gen_08b39300bd5a990713b885b905ad5e76 | TCR/BCR repertoire sequencing in the conjunctival associated lymphoid tissue from trachoma longitudinal studies | Wellcome Trust | Kilimanjaro Clinical Research Institute | HRCS22_14515 | The primary aim of this study is to use next generation sequencing to investigate the T and B cell receptor repertoire in the conjunctival tissue in those susceptible to repeated ocular infection with Ct and those resistant despite similar exposures.RNA samples selected from archived conjunctival swab samples from a 4-year longitudinal study of children with progressing trachomatous scarring and non-progressing will be used. Sequences will be aligned to their germline V-, D-, and J-genes and assigned according to the IMGT/GENE-DB reference directory. The average length of CDR3 regions, as well as the frequency of shared CDR3s will be compared. The usage of specific V genes, families and their frequency will also be compared. Initial analysis will be conducted on 25 progressors and 25 non-progressors at the final time points. Based on the results of the data obtained, a sufficient number of samples will be selected for further analysis from earlier timepoints in the cohort. The project has the potential to contribute toward the evaluation and progression of current and future human clinical trials of Ct vaccines. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_628936e225e8ce1e53b5f817c02a3975 | Can patients understand and use regulatory results? Investigating the influence of risk-rating of health facilities on community engagement and accountability mechanisms in two Kenyan counties. | Wellcome Trust | Strathmore University | HRCS22_14529 | Strategies to address poor implementation of health facility regulation in developing countries have mainly been supply driven, with the emergence of innovative risk-based regulatory frameworks that respond to facility performance. However, there has been less emphasis placed on demand side strategies, with little known about how such regulatory innovations have utilized community accountability and engagement mechanisms to improve quality of care. This study seeks to investigate how regulatory risk-rating of health facilities feeds into community engagement and accountability mechanisms. It will involve: (i) a review of literature to understand links between community engagement and accountability, and health facility regulation; (ii) a quantitative survey to investigate the association between regulatory performance ratings and patients’ perception of quality of care at healthcare facilities; and (iii) in-depth interviews to determine whether and how regulatory performance rating of facilities is understood and used to influence care through community accountability and engagement mechanisms. The study findings will inform policy on how to increase public engagement/involvement in health facility regulation and how to capitalize on community accountability mechanisms to improve services | 8.1 Organisation and delivery of services | 6project_grants_public
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gen_7d7703d8081cd739ecd5c00de6e56ebc | S100A9-dependent radiation resistance in brain metastasis | Worldwide Cancer Research | Spanish National Cancer Research Centre | HRCS22_14537 | With the advent of improved diagnosis and novel therapeutic approaches cancer patients live longer with systemic disease. However this increased survival is paradoxically associated with a growing incidence of brain relapses. Brain metastasis remains an unmet clinical need with limited therapeutic possibilities. Among them, brain irradiation has been applied for decades yet its efficacy to improve the course of the disease is controversial. Why radiation therapy does not yield better responses given its probed ability to penetrate the brain?. We want to perform in vivo experiments to test a biomarker of radiation resistance that we have discovered using a non-biased approach. This biomarker could be particularly important in situ. Consequnetly, our approach will use advanced models of brain metastasis from breast and lung cancer, including immunosuppressed models but also newly established immunecompetent ones and brain metastasis PDX. We present a research proposal by which, in collaboration with clinicians, we will be able to evaluate the translational potential of a biomarker to predict responses to radiation therapy, thus offering the possibility to personalized this therapeutic approach. In addition, to improve the efficacy of radiotherapy without inducing neurotoxicity, we will use a BBB-permeable drug that blocks the signaling pathway inducing therapeutic resistance downstream of the biomarker. Our proposal is based on strong preliminary data, leading expertise in brain metastasis research and experienced clinical collaborators that will allow us to make a significant contribution on the poorly defined biology of therapeutic resistance of brain metastasis. | 5.1 Pharmaceuticals | 6project_grants_public
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gen_933e86855997b917fc5124c8a13c01a0 | Interaction between ionising radiation and genetic susceptibility in the aetiology of childhood acute lymphoblastic leukaemia | Children with Cancer UK | Yale University | HRCS22_14562 | The aetiology of childhood acute lymphoblastic leukaemia (ALL) is largely unknown. Various studies have evaluated the role of ionising radiation and genetic susceptibility, but potential interaction between the two factors has rarely being examined. A major barrier to this type of research is the limited availability of both radiation and genetic data in existing studies. In the proposed project, we will leverage three studies from the Childhood Leukaemia International Consortium (CLIC), including the California Childhood Leukemia Study (CCLS), the Children’s Cancer Group (CCG) study of childhood ALL, and the Australian Study of Childhood ALL, to assess gene-radiation interaction in the aetiology of childhood ALL. Specifically, we will use the CCLS as the discovery/training dataset and the CCG and Australian studies as validation datasets. The CCLS has a case-control design (746 cases and 734 controls), while the CCG (n = 507) and Australian (n = 602) studies have a case-only design. All studies have collected very similar data on diagnostic X-rays that a child received before the diagnosis of ALL (and comparable date for controls), as well as whole-genome genotyping data. After conducting rigorous quality control, we will use both benchmark logistic-regression based analysis and more advanced regularization-based G-E interaction analysis methods recently developed by Co-Applicant Dr. S Ma’s group and others. With 2,589 subjects, the proposed project will provide an unprecedented opportunity to elucidate the potential aetiological role of gene-radiation interaction. Our findings will help clarify the biological pathways in leukemogenesis and identify children at high risk for ALL. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_1a14c3e52ee2eb84f53dcf11c2d4618e | Systemic Inflammation and Growth following Acute Illness in Children. | Wellcome Trust | KEMRI Wellcome Trust Research Programme | HRCS22_14572 | Medical and nutritional management in acutely-ill undernourished children in developing countries aim to support rapid weight gain. However, such children remain at risk of death and poor catch-up growth post-hospital discharge. Little is known about mechanisms regulating childhood growth after acute illness. I hypothesise that persistent systemic inflammation (SI) is a key determinant of growth post-discharge among undernourished children. SI is associated with reduced linear growth in community cohorts, and is demonstrable at hospital discharge among undernourished children, potentially indicating untreated infections, microbiota dysbiosis, gut-circulation microbial product translocation, or enteric inflammation. My proposed work is nested within the CHAIN cohort that aims to characterise modifiable risks for mortality among acutely-ill children <2 years old in six countries in Africa and Asia. I aim to investigate whether persistent SI is a key determinant of catch-up growth among undernourished children and investigate its causes. I will examine relationships between growth and markers of SI, blood metabolomic profile, growth mediators, and microbial exposures comparing with well community children through a collaborative network between KEMRI-Wellcome; Kenya, the University of Oxford and the Wellcome Sanger Institute. Better understanding of relationships between SI and post-discharge growth is expected to inform therapeutic strategies to improve recovery. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_2719cf11c622436d56e731beeaa8381c | Uncovering chromatin aberrations and molecular mechanisms associated with Alternative Lengthening of Telomeres in cancers | Worldwide Cancer Research | Monash University | HRCS22_14594 | Cancer cells gain replicative immortality by activating one of two telomere maintenance pathways. The aberrant ALT (alternative lengthening of telomeres) pathway is found in 15% of cancers. Recent studies have identified chromatin factor ATRX and histone H3.3, which are frequently mutated in ALT cancers to be the key contributors to the ALT process. This breakthrough finding was facilitated by our original discoveries describing the roles of ATRX and H3.3 in controlling telomere function. Developing treatments for ALT cancers is challenging because of the current poor understanding of the molecular mechanisms underlying ALT activation and maintenance. This proposed study aims to uncover the molecular events and chromatin aberrations linked to ATRX/H3.3 mutations and ALT by pursuing the following aims. First, using the ALT cell models we have created, we will perform in-depth chromatin and genomics analyses to explore how a disrupted KDM4 network drives ALT and oncogenesis in ATRX/H3.3 mutant cancers. This follows from our recent discovery that mutant H3.3 protein inhibits the function of KDM4 histone demethylases and this leads to substantial genome-wide changes in chromatin and transcription profiles. Second, we will perform proteomics analyses to identify new protein factors and regulatory pathways driving and sustaining ALT. These studies will uncover new insights into the ALT pathway and identify new therapeutic targets for ALT cancers. | 1.1 Normal biological development and functioning | 6project_grants_public
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gen_3141ea7fea4ccb9825c828fbce540783 | Biomimetic nanocarriers for boosting chemotherapy by restoring breast cancer immunosurveillance | Worldwide Cancer Research | National Research Council | HRCS22_14604 | Triple-negative breast cancer (TNBC) still lacks effective treatment options; thus, innovative targeted therapies are urgently needed to tackle this disease. Emerging evidence suggests that chemotherapeutic drugs, including paclitaxel (PTX), can re-establish immunosurveillance by inducing immunogenic cell death (ICD) at the tumour site. Immune modulators are known to additionally boost ICD; in particular, clinical studies reveal that inhibitors of the indoleamine 2,3-dioxygenase (IDO1) pathway enhance the efficacy of traditional chemotherapeutics. However, poor bioavailability, off-target effects and difficulties in achieving therapeutic drug concentrations at the target tissue still hamper the breakthrough of this combined treatment. We hypothesise that a specifically-devised biomimetic, bioresponsive and dual-loaded nanosystem will enhance both the antitumor cytotoxicity and the ICD effect of PTX by reversing the immunosuppressive effects of IDO1 overexpression at the breast cancer site. To demonstrate this hypothesis, we designed an innovative and biomimetic nanobinder (NB) constituted by a finely-tuned combination of redox-responsive PTX and IDO1 inhibitor prodrugs, and able to selectively reach the TNBC tissue by its preferential binding with endogenous human serum albumin (HSA). The specific aims of this proposal are: (i) to synthesize NBs containing an effective combination of PTX and IDO1 inhibitor prodrugs; (ii) to characterize their physicochemical properties, plasma stability and HSA selectivity; and (iii) to assess their ability to revert immune-tolerogenic effects and enhance antitumor efficacy in vitro. Our innovative and highly modular NB approach yearns to improve TNBC treatment and patient compliance by exploiting its unique features. This approach might also be applied to other solid tumours, paving the way for new therapeutic strategies in other oncological areas. | 5.1 Pharmaceuticals | 6project_grants_public
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gen_7f78e4335db3742c7f9a2face5afc17c | Improving anti-cancer therapy by stromal remodelling | Worldwide Cancer Research | University of Western Australia | HRCS22_14611 | Despite recent breakthroughs, cancer immunotherapy remains challenging. One of the problems is that anti-tumour T cells - even when activated - do not reach the cancer core in sufficient numbers to be effective. The lead investigator’s laboratory has pioneered the field of tumour blood vessel normalization which significantly enhances T cell penetration into solid tumours, with proven anti-cancer effects. For clinical translation, mechanistic insights into these complex processes are urgently required. In this project, substantial preliminary data demonstrate an innovative and new approach to remodel the vascular bed, restore vessel integrity, improve tumour perfusion and enable massive lymphocyte influx into tumours. We will use mouse models of melanoma, including patient-derived melanoma xenografts in immune ‘humanized’ mice, to provide new insights into stromal remodelling and immune cell trafficking. Importantly, mechanistic insights will enable re-positioning of established drugs/small molecule inhibitors to specifically improve vessel function. Furthermore, we will evaluate drugs in the context of durable intratumoral effects, low toxicity and enhanced efficacy in immune combination therapies. | 5.1 Pharmaceuticals | 6project_grants_public
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gen_98c2be89a58e6515e653cec05d073e85 | Checkpoint receptors expressed by dendritic cells- do they play a role in immunotherapies? | Worldwide Cancer Research | Monash University | HRCS22_14612 | The preliminary data of this proposal indicate that PD-1 and other checkpoint inhibitors are upregulated on DC upon activation both in vitro and in vivo. The panel of immune checkpoint proteins expressed by DC is governed by their specific subset. Moreover, human DC subsets show similar upregulation of PD-1 upon activation. Our examination of DC of PD-1 knockout mice has revealed that this protein is involved in the regulation of interferon-lambda production by DC subsets and in the T cell stimulation capacity of DC. This is particularly striking in the cross-presenting CD8+ DC, also known as conventional (c) DC1. Moreover, blocking of PD-1 signalling on human DC using small molecule inhibitors of PD-1 also leads to enhanced IFN-lambda producing capacity of cDC1. This project aims to decipher exactly how PD-1 signalling in DC affects transcriptional regulation and overall function in these cells. We will determine the PD-1 expression on DC in mouse models of induced melanoma. We will determine how PD-1 expression on DC determines outcome of melanoma growth pre and post treating with PD-1 blocking agents. Our work will reveal the functional significance of PD-1 expression by DC, revealing for the first time how these cells must be taken into account when designing immune checkpoint immunotherapies. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_c9a30fac9104c7e87c823a49a96cf428 | The Development and Optimization of Anti-CLEC12A Targeted Umbilical Cord Blood Derived CAR-NK Cells in Acute Myeloid Leukaemia. | Wellcome Trust | National University of Ireland, Galway | HRCS22_14640 | Acute myeloid leukaemia (AML) is an aggressive form of blood cancer. Current chemotherapy-based treatments cure less than half of all patients with AML. In many cases a relapse occurs which is very difficult to treat effectively. ‘Leukaemia stem cells’ which resist the effects of chemotherapy are an important cause of AML relapse. New treatments which can target and destroy these cells may reduce the risk of relapse and increase cure rates. In certain other forms of blood cancer new treatments called CAR-T cell therapies have been very effective. These treatments retrain a patient’s immune cells (T-cells) to recognise cancer cells. These treatments are harder to develop for AML as it is difficult to identify a suitable target on the cells for immune attack. In this project we are developing a therapy using ‘retrained’ natural killer cells (CAR-NK cells) which recognise AML cells and leukaemia stem cells. The target for the CAR-NK cells is a protein called CLEC12A. We are also investigating ways of improving the ability of these CAR-NK cells to recognise and destroy leukaemia cells. One example of this is combining CAR-NK cells with medications or changing their genetic code to further boost their activity. | 5.2 Cellular and gene therapies | 6project_grants_public
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gen_26d8d9c5ca6751ccfdad78059825d22b | The Impact of Intensive Medical and Surgical Control of Diabetes on Experimental Rodent Diabetic Kidney Disease. | Wellcome Trust | University College Dublin | HRCS22_14641 | Background: Kidney disease affects 12 in every 100 people, most commonly due to diabetes. Kidney damage due to diabetes often persists despite treatment with the best available drugs. Most people with kidney damage from diabetes are overweight. Drug and surgical weight loss treatments help overweight people to lose more weight for longer periods of time, improve quality of life, and reduce the chance of dying. Helping people with diabetes to lose weight also slows kidney damage. How this happens remains poorly understood. Approach: We will study kidney damage caused by diabetes in rats as they age. We will also treat rats with diabetic kidney damage with drug and surgical obesity treatments to better understand how weight loss protects kidney tissue. Expected Impact: We will present our results at international scientific meetings and publish our results in scientific papers. We will present our results to patients attending our dedicated weight loss clinic for people with kidney disease, and involve patient stakeholders in planning future studies. Our studies may result in more people with diabetic kidney damage receiving weight loss treatments and may highlight important targets for new therapies for diabetic kidney damage. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_aef73df45e332860f7b17c38d880b6c1 | Respiratory immune responses and their interaction in control of nasal colonization with Bordetella pertussis and Staphylococcus aureus in humans | Wellcome Trust | Trinity College Dublin | HRCS22_14642 | This research study is designed to examine how the human immune system responds to different types of vaccines and to bacteria that commonly live in the nose, in particular Bordetella pertussis and Staphylococcus aureus. Infection with the bacteria Bordetella pertussis (‘B.pertussis’) causes whooping cough. Vaccines are routinely given in childhood to prevent whooping cough. If you received routine childhood vaccinations you will have received one of two B.pertussis vaccines depending on your year of birth. This study aims to look at how the human immune system responds to different types of B.pertussis vaccines that are or were in routine use. Another important bacteria which may cause disease in humans is Staphylococcus aureus (‘S.aureus’). Approximately 20-30% of healthy people carry these bacteria in their nose without it causing infection. This is called colonisation. However, in some people, infection with S.aureus can be potentially serious and require prompt treatment. This study aims to look at the differences in how human immune system responds in people who are colonised with S.aureus and those who are not. It is hoped that this research will contribute to future work on vaccines that may benefit vulnerable patients susceptible to serious infections with both S.aureus and B.Pertussis. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_3bfcdf8a0ac8d0a2c4140098c49303f7 | Investigation of the role of the VWF-ADAMTS13 axis in the pathogenesis of sickle cell vasculopathy in children | Wellcome Trust | Royal College of Surgeons in Ireland | HRCS22_14643 | Sickle cell disease (SCD) is responsible for major global morbidity and mortality and more than 1,000 SCD children are born every day. Globally over half will die before five years of age and <10% survive to adulthood. Even in developed countries, SCD causes significant morbidity with 10% of US patients developing strokes and potentially lifelong disabilities. The World Health Organisation and United Nations have recently designated SCD as a global health priority, highlighting the need for research into the biological mechanisms underlying SCD. A critical step in blood vessel blockage in SCD involves sickle red cells sticking to the blood vessel wall. Interestingly, evidence suggests a new role for the plasma clotting protein von Willebrand factor (VWF) in this process with increased VWF and reduced levels of ADAMTS13, the main protein responsible for breaking down VWF. This study aims to define the molecular mechanisms underlying blood vessel blockage in SCD, including how VWF and abnormally large forms of VWF, influence paediatric SCD biology. We will specifically investigate the hypothesis that sickle red cell occlusion is promoted by a dysfunctional VWF-ADAMTS13 axis, leading to characteristic clinical complications. novel findings from this research may inform future treatments to improve clinical outcomes. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_16313cecfacd60dce54a59a7200a6ab9 | Clinical ApplicatioN of DEep Learning and Intelligent Vision in Radiology: CAN DELIVeR | Wellcome Trust | University College Dublin | HRCS22_14646 | The workload associated with medical imaging has greatly increased both in terms of volume and complexity in recent years. The amount of clinicians trained in expert interpretation of these data has however, failed to keep pace with demand. This project encompasses the application of Machine Learning to specific radiology use cases. Imaging with MRI is the cornerstone of surveillance of patients with MS and underpins decision making around initiation of and modifications to therapy Reporting these images is a significant proportion of the reporting time of our Neuroradiologists. Artificial Intelligence, and especially machine and deep learning have been proposed as a potential solution. Computer Science (CS) groups who aim to tackle these issues may fail due to a lack of access to clinical insight and clinical data. Furthermore clinical groups may lack the CS expertise. Presently in Ireland there is no framework for clinicians with medical imaging problems, which could potentially be solved with machine vision, to interact with computer scientists with the expertise to solve these problems. We intend to apply solutions using novel computer science techniques to clinical problems with a particular focus on the assessment of interval change between scan acquisitions. | 4.1 Discovery and preclinical testing of markers and technologies | 6project_grants_public
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gen_d81980f4a6017cc9992fe030943f0e12 | The DRPLA Natural History and Biomarker Study | Ataxia UK | New York University | HRCS22_14659 | The DRPLA Natural History and Biomarker Study aims to longitudinally collect data in patients affected by DRPLA and gather information from different biomarker modalities in order to facilitate the implementation and development of clinical trials. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_b0e61ed78477fffa2af2b86937163404 | Ultrasensitive assays for tau and aSyn aggregates in AD and PD | Alzheimer's Research UK | Case Western Reserve University | HRCS22_14667 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public
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gen_ad0a0c66daf52c6eac2da8d42d88c79a | Innate Immune Response | Duchenne UK | Binghamton University | HRCS22_14697 | Targeting the innate immune system to block acute inflammatory and chronic immune responses to transgene and AAV vector in DMD | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_efd137ca5ccbda2299546622d16a7299 | Immunological pathways in Hidradenitis Suppurativa and potential therapeutic targets. | Wellcome Trust | University College Dublin | HRCS22_14698 | Hidradenitis Suppurativa (HS) is a chronic skin condition consisting of abscesses, boils and sometimes scarring in the groin, armpits and under the breasts. It has a severe impact on quality of life. There is dysregulation of the immune system. There is only 1 licensed treatment for moderate to severe HS, adalimumab, a TNF-α inhibitor. It is effective in 50% of patients. This project aims to improve the understanding of the role of the immune system in HS. We will compare the immune profiles in patients skin and fluid collected from their skin, before and after treatment with adalimumab, to try to identify differences in patients who respond and those who don't. We will compare HS immune profiles to patients with psoriasis, atopic eczema and healthy controls. We will also look at targeting IL-17 and IL-23 as potential therapeutic options. A final part of the study will look at the use of metformin to treat HS. Approximately 50% of HS patients have metabolic syndrome. Metformin is a useful treatment for HS but little is know about how or why it works. We will look at its effect on HS, metabolic markers, inflammatory markers, as well as skin and blood cytokines. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_b700854eead57b82316c5ec6ecbe39e8 | Plasma glycated CD59 (gCD59), a Novel Biomarker for the Diagnosis, Management and Follow up of Women with Gestational Diabetes (GDM). | Wellcome Trust | National University of Ireland, Galway | HRCS22_14699 | The frequency of diabetes diagnosed during pregnancy is increasing. The diagnosis for diabetes in pregnancy (DIP) is very long, cumbersome and inconvenient for most women. CD59 is a new blood test that has been shown to be more elevated in people with diabetes than in people without diabetes. The purpose of this study is to examine if this new blood test can predict the development of DIP (the blood test will be done in the first trimester of pregnancy), can diagnose DIP (the blood test will be done in the second trimester of pregnancy at the same time with the current diagnosis test), can predict pregnancy-related complications for both mother and baby, can asses the efficacy of treatment in DIP (the blood test will be done in the third trimester of pregnancy) and can predict the development of diabetes after delivering the baby (the blood test will be done at the 6 weeks follow-up for all women with DIP). This new proposal addresses a major public health concern, is supported by previous research on human indicating that CD59 is a new emerging blood test with large potential to diagnose and monitor DIP | 4.1 Discovery and preclinical testing of markers and technologies | 6project_grants_public
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gen_76eddd47b388a569f98e3426cef4c7a1 | DRPLA Natural History and Biomarkers Study (DRPLA NHBS) | Ataxia UK | University of North Carolina at Charlotte | HRCS22_14709 | Currently, there is no effective treatment for DRPLA, this study objective is to obtain natural history data of the condition, and valid biomarkers, which can be used as outcome measures in order to facilitate the implementation and development of clinical trials. This study will collect longitudinally clinical measures in patients affected by DRPLA and gather information from different biomarker modalities. The study design is prospective, observational, longitudinal, multi-national, multi-center study, in subjects with confirmed DRPLA-mutation carrier and a volunteer unaffected control group. The study aims to recruit 150 DRPLA participants and 75 unaffected controls. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_9f4cedcb36809eb64cd171e83fc2080c | Improving help-seeking for depression care in Nepal: Development and testing the feasibility, acceptability and appropriateness of a social contact-based community intervention | Wellcome Trust | Transcultural Psychosocial Organization (TPO) Nepal | HRCS22_14712 | Depression is a highly prevalent mental health condition which has enormous emotional and financial burden on individuals, families, and society as a whole. Despite the availability of effective treatment, a large number of people needing depression care do not receive treatment. Individual often delay or avoid seeking help for depression due to various reasons including stigma and negative attitude towards services. The aim of this study is to develop and test the feasibility, acceptability, and appropriateness of a social contact-based community psychosocial intervention in order to improve help-seeking behavior of people with depression in Nepal. The objectives of the study are to; (1) systematically review the interventions that have shown effectiveness to improve help-seeking attitude, intension, and behavior among people with depression in LMICs; (2) assess the perceptions of people with depression, their family members and key community stakeholders about barriers for seeking depression care and potential strategy to address those barriers; (3) develop a social contact-based community psychosocial intervention in order to improve negative attitude and intention towards seeking depression care; and (4) test the feasibility, acceptability, and appropriateness of the social contact-based community psychosocial intervention through a pilot cluster randomized controlled trial in Jhapa district of Nepal. | 6.6 Psychological and behavioural | 6project_grants_public
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gen_071f04665f6d3fae7e03ae4942d6741a | Improving Understanding of the Biological Basis of Tinnitus: A Multi-Omics Approach in Two Large Cohorts of Women | Royal National Institute for Deaf People | Brigham and Women's Hospital | HRCS22_14716 | There is a critical need to improve understanding of the biological basis of tinnitus, unravel the diverse etiologies that underlie this heterogeneous condition, and advance development of tailored treatments based on a precision medicine data-driven approach. Accumulating evidence suggests complex interactions between genetic, demographic, lifestyle and other environmental factors influence the generation of tinnitus. Our objectives are to identify a metabolomic signature of tinnitus and to use a multi-omics approach to bridge tinnitus-related metabolomic data with genomic data and data on a wide array of individual, lifestyle and environmental factors. We will interrogate metabolite profiles using targeted and untargeted discovery approaches to develop objective tinnitus biomarkers and advance understanding of tinnitus pathogenesis. We will leverage the extensive longitudinal data collected in 2 large U.S. cohorts with long follow-up, the Nurses’ Health Studies I and II, to conduct network analyses that integrate these data with our wealth of hearing-related and non-audiological phenotypic data to study the biological basis of tinnitus. We will include all participants with tinnitus and existing metabolomics data (n=4,855), adding additional participants as data accrue. We aim to: (1) identify a set of metabolites that can act as a biomarker of tinnitus (“metabolomic signature”), (2) identify plasma metabolites associated with risk of incident tinnitus, and (3) employ a network approach to interrogate tinnitus genotype-metabolomic-phenotype relationships. Our multidisciplinary approach could elucidate pathogenic changes that lead to tinnitus, provide insight into the classification of subtypes of this heterogeneous disorder, identify potential treatment targets, and inform the development of personalized therapeutics. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_c5bd1db0f17656ba5b0ff1a990f0a4ea | Understanding and addressing intimate partner violence (IPV) in forced migrant (refugee) communities in Durban, South Africa | Wellcome Trust | South African Medical Research Council | HRCS22_14723 | Forced migrants’ health is a global concern, especially because forced migration is expected to increase substantially driven by war and human caused climate change [1]. In South Africa, there are approximately 2.1 million forced migrants (refugees). This population experiences poor health, driven by exposure to violence, and xenophobia, which further limits access to health care. High rates of intimate partner violence (IPV) have been found among these population [2]. However, little is known about how gender inequalities, xenophobia, and experiences of forced migration, intertwine to shape IPV among forced migrants. This innovative study uses a mixed methods approach and co-development process with young (18-30) forced migrants to understand and then address IPV in forced migrant communities in Durban, South Africa. I will first, using qualitative and quantitative data describe these issues, then co-develop with Youth Peer Research Associates (YPRAs), who are forced migrants themselves, an intervention to address IPV. Finally, I will assess the intervention’s feasibility and acceptability with young (18-30) forced migrants. I will also, together with YPRAs, engage extensively with forced migrant communities, advocacy groups, and government, ensuring research translates to policy change. Study results will inform the co-design of a pilot RCT with this population. | 8.1 Organisation and delivery of services | 6project_grants_public
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gen_905a99b6e29893f437298a2ae02f4a33 | Investigating the Impact of the International Response to the 2014 West African Ebola Crisis | Wellcome Trust | University of Cape Town | HRCS22_14728 | The 2014 West African Ebola crisis was the deadliest outbreak in this region. While the international response was delayed, eventually international actors, including scientists, clinicians, NGOs, and governments came to the aid of affected countries. What remains unclear is the impact of the international response on key African actors and institutions. This project will investigate the impact of the international response on the visibility, agency and capacity of African scientists, researchers and other key stakeholders. Through a social network analysis, using authorship and institutional affiliations, this project will map scholars contributing to the global discourse on Ebola. Additionally, a scoping review will be used to determine how the crisis of Ebola was framed. Combined, they may suggest the relative power African scientists had in shaping the scientific dialogue around this epidemic. This project will also conduct interviews with key stakeholders such as scientists, researchers, and policy makers in Nigeria, Sierra Leone and Liberia. Regional actors based at Africa CDC, will also be included. These interviews will provide important perspectives from key African actors about how the international response to the Ebola crisis, impacted on their agency, capacity and visibility during and after the crisis. | 8.3 Policy, ethics and research governance | 6project_grants_public
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gen_f6c305639ac24b0bbc32cf0043d482b3 | MGMT methylation score for predicting benefit from TMZ in patients with IDHmt low grade glioma to guide treatment decisions | The Brain Tumour Charity | University Hospital of Lausanne | HRCS22_14735 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public
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gen_02c086ece0e988ae90314066587c1697 | Mindscapes Curatorial Research Fellow | Wellcome Trust | Humboldt-Universität zu Berlin | HRCS22_14768 | Mindscapes Curatorial Research FellowFull-time position with CARMAH, reporting to the DirectorThis post-doctoral fellowship appointment will assist with the research and development phase of a new project looking at aspects of mental health with a specific focus on Berlin. Alongside pursuing self-directed research, the fellow will work closely with members of Wellcome’s International Cultural Programmes team and Wellcome’s Germany Office under the direction of the International Cultural Producer Danielle Olsen to: - Develop external partnerships across the city with partner organisations on the theme of mental health in Berlin investigating potential archives, collections, institutions and community led organisations that could provide a focus for transdisciplinary research - Serve as connector across participant spaces and places, developing creative new links with international city partners (in Bengaluru, New York and Tokyo) as the project develops - Assist in developing interdisciplinary and inclusive methods and processes between and across the Arts and Sciences on a mental health theme - Participate in a launch meeting in July 2021 on a mental health theme with a Berlin City focus - Explore crossover and hybrid experimental curatorial possibilities utilizing original creative work, events, and public programming. | 8.1 Organisation and delivery of services | 1fellowships_scholarships
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gen_06d61076710ed2db713f754d3a0c929d | Developing optimized implementation strategies to improve the efficiency of genetic control approaches against malaria vectors in Burkina Faso. | Wellcome Trust | Centre National de la Recherche Scientifique et Technologique | HRCS22_14833 | Genetic control approaches through application of CRISPR/Cas9-based gene drives represent a promising strategy to control vector borne diseases such as malaria. While the technology is still being optimized, there is urgent need to address several knowledge gaps crucial for safe and effective field implementation. One of the most important need is to elucidate ecological processes that will influence spread and persistence of transgenes in wild mosquito populations; such as mosquito migration and aestivation. This research project aims to understand these phenomena with the objective of developing a reliable field data-based predictive model of transgene diffusion in the field. Short and long-range migration, aestivation and spatial population dynamics of An. gambiae (s.l.) will be explored in a group of village clusters in Burkina Faso, to understand their relative contribution to the sustainability and spread of malaria mosquitoes across different ecological settings. Activities will include sequential mark-release-recapture experiments to quantify and characterize dispersal and survival using long-term marking approaches and entomological surveillance to measure spatial population dynamics and highlight the role of aestivation. All these data will be used to inform and build accurate modelling tools for vector control. Keywords: Genetic control, Gene drive, Mosquito migration, Mosquito aestivation, Mark-Release-Recapture, predictive model. | No Research Activity assigned | 6project_grants_public
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gen_2e06fceaa03e09995e0c519a7a4a73c1 | Developing and pretesting a sexual reproductive health and rights (SRHR) school health promotion intervention to reduce sexual transmission of HIV in a high-burden rural setting in KwaZulu-Natal | Wellcome Trust | Africa Health Research Institute | HRCS22_14838 | Adolescents in SA face huge, interlinked epidemic of poor sexual reproductive health (SRH) and high HIV-incidence. Innovative approaches to improve demand and uptake of SRH and HIV-prevention is critical. Schools present an opportunity to deliver effective health-interventions within sustainable infrastructure. The aim of this work is to adapt and evaluate a scalable and sustainable school health-promotion intervention to improve SRH and HIV-prevention uptake amongst 15-19-year-old learners in rural KZN. I hypothesize that an adapted multi-component SRH programme integrated with biomedical interventions delivered to learners will improve SRH and HIV-prevention uptake in a high HIV-burden rural KZN district. I will use the MRC-framework for the development and evaluation of complex interventions to guide this work and a mixed-method study design to address the research questions. I will use participatory research methods to inform the contextual adaptation, integration of biomedical HIV-prevention and refining of the SRH intervention. I will pilot and assess the acceptability and feasibility of the adapted intervention using process evaluation and pre and post surveys to measure changes in self-reported SRH and HIV-risk behaviours. Further, I will provide exploratory data on the effect of the intervention on improving uptake of SRH and biomedical HIV-prevention using clinical linkage data. | 3.1 Primary prevention interventions to modify behaviours or promote well-being | 6project_grants_public
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gen_8e7131b42ee9cc353a12af84c8e8e768 | Pharmacometrics to advance novel regimens for drug-resistant tuberculosis (PandrTB) | Wellcome Trust | Institute of Tropical Medicine Antwerp | HRCS22_14841 | PandrTB is a study of the pharmacokinetics(PK) and pharmacodynamics(PD) of bedaquiline, delamanid, clofazimine, linezolid, moxifloxacin, levofloxacin and pyrazinamide used in novel combinations to treat multidrug-resistant tuberculosis(MDR-TB). PandrTB is nested in the endTB trial, a randomized study that will evaluate five 9-month, injectable-sparing regimens that could transform the treatment of MDR-TB. Nonlinear mixed-effects models will describe the population PK of the drugs and treatment response of Mycobacterium tuberculosis(Mtb) load over time. Recursive partitioning methods will evaluate baseline MICs and PK measures as drivers of treatment response (PD model parameters, time to culture conversion, longer-term outcomes, acquisition of phenotypic resistance). Thus the key drugs and drug exposure thresholds for activity will be defined, and exposure-dependent synergy or antagonism identified. Toxicities will be assessed and the risks of toxicity estimated, by drug exposure and important comorbidity (including HIV infection). To advance the understanding of drug penetration, we will develop approaches to measure free drug plasma concentrations. Drug-drug interactions will be described. Simulations will predict optimal doses. Thus PandrTB will inform how best to use these new and repurposed drugs in combination, to create the most effective and least toxic regimens while minimizing the development of further drug resistance. | 5.1 Pharmaceuticals | 6project_grants_public
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gen_63b76ed3338a0d7c5b8bf54fe22e7406 | DNA damage-induced nuclear envelope (NE) rupture is a new vulnerability of homologous recombination (HR)-deficient cancers | Worldwide Cancer Research | Institute Curie | HRCS22_14878 | No abstract available for this analysis. | HRCS Research Uncodeable | 6project_grants_public
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gen_3c18396b007dcbffbb7500925cfe5e39 | Advancing product development and use of monoclonal antibodies for infectious disease in low and middle income countries (LMICs)’ | Wellcome Trust | World Health Organization | HRCS22_14879 | The project supports activities in the Immunization, Vaccines and biologicalsdepartment of the WHO that aim to advance the product development and use ofmonoclonal antibodies (mAbs) for infectious diseases, with a focus on meeting theneeds of Low and Middle Income Countries (LMICs). Three specific activities will becarried out. First, a stakeholder consultation on monoclonal antibody technologies willbe held to discuss which would best support affordability and accessibility in LMICs.Second, an application to establish rabies mAbs on the WHO model list of essentialmedicines (EML) would set the precedent for inclusion of additional infectious diseasesmAbs in the future. Thirdly, an assessment of diphtheria immunoglobulin supply andpotential demand for mAb-based products will be carried out which could serve as amethodology to be used to assess other mAb based products.” | No Research Activity assigned | 6project_grants_public
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gen_74f9bce0887d516c6da16dd4a1b90732 | Development of Nanoparticle Antibiotic Adjuvant for the Treatment of Chronic Suppurative Otitis Media | Royal National Institute for Deaf People | Stanford University | HRCS22_14902 | We request support to investigate the use of functionalized gold nanoclusters as an adjuvant therapy for chronic suppurative otitis media (CSOM). CSOM is characterized by a chronically discharging infected middle ear that is most frequently caused by Pseudomonas aeruginosa (PA) and Staphylococcus aureus and is a leading cause of permanent hearing loss. In CSOM, PA exists in bacterial communities known as biofilms. Fluoroquinolone eardrops are the primary method of treatment; however, this treatment is ineffective in fully eradicating the infection because of the inability of fluoroquinolones to target a subpopulation of metabolically inactive bacteria known as persister cells within the biofilms. Persister cells repopulate the biofilm niche after therapy discontinuation, causing relapse of CSOM. The result is multiple rounds of surgery and a lifelong struggle with CSOM. There is a large unmet need to develop new medical therapies aimed at persister cells in biofilms of CSOM. Our lab recently created a novel PA CSOM animal model with bioluminescent strains of PA and validated it as mimicking human disease in chronicity, fluoroquinolone therapy recalcitrance, and hair cell death (hearing loss). We have created an anionic hydrophilically functionalized gold nanocluster covalently conjugated with cell penetrating peptide (AuNC@CPP) as an adjuvant for fluoroquinolones. Co-administration of the AuNC@CPP with ofloxacin completely eliminates persister cells in both stationary phase and biofilms of PA in vitro. The proposed work will develop the first adjuvant therapy that specifically targets recalcitrant CSOM and lays the foundation for future research of this treatment in other chronic biofilm infections. | 5.1 Pharmaceuticals | 6project_grants_public
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gen_de3cc0f9b634dff35a9965c7ca648cdd | Mapping the miRNA atlas of CF airway epithelial cells using patient-derived gene-edited iPSC | Wellcome Trust | Royal College of Surgeons in Ireland | HRCS22_14903 | CF is the most common lethal monogenic disease in Caucasians with F508del being the most common mutation (>80%). MicroRNA (miRNA) have emerged as key players in disease pathogenesis and are differentially expressed in the CF airway epithelium. Current in vitro models of CF do not represent the genetic background of individual patients and primary cells such as human bronchial and rectal epithelial cells are acquired by invasive procedures. Induced pluripotent stem cells (iPSC) represent an attractive tool to advance the understanding of CF given their capacity to generate large quantities of cells that can be shared, stored, gene-edited and differentiated into various cell types. Here, I propose to employ an iPSC model that reflects a patient’s unique genetic background, CF mutation and can be directed towards mini-lung organoids using established differentiation protocols to examine the role of miRNA in the pathogenesis of CF lung disease and ultimately advance molecular characterisation of CF. Key goals include, examination of differential miRNA expression in a patient derived CF and CF-corrected iPSC paediatric model of airway organoids and investigation of downstream miRNA:Target expression networks and their relationship to CFTR with a view to exploration of adjunct therapies to existing CFTR modulator drugs. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_12830ba0b84652dc3700dad5ffac3080 | Optimization and pharmacokinetics of allele-specific antisense oligonucleotide therapy for late-onset sensorineural hearing impairment DFNA9 | Royal National Institute for Deaf People | Radboud University Nijmegen Medical Centre | HRCS22_14927 | BACKGROUND: Hearing loss (HL) is the most prevalent and disabling sensory deficit worldwide. The c.151C>T founder mutation in COCH (DFNA9) is amongst the most important causes of (dominantly) inherited, adult-onset HL and affects >1,500 Dutch and Belgian individuals. Hearing aids or cochlear implants can relieve part of the burden of HL, but the perceived quality is no match for natural hearing. Genetic therapies that can halt disease progression or prevent hearing impairment altogether, are therefore urgently needed. AIM AND APPROACH: We previously published antisense oligonucleotides (ASOs) that can specifically target mutant COCH transcripts for degradation by RNase H1. We will further develop our lead ASO for DFNA9, and address important knowledge gaps regarding the safety and feasibility of the application of AON-based therapies in the adult inner ear. We formulated four research objectives: 1)Optimization of lead molecule “COCH c.151C>T ASO-E”. 2)Evaluation of molecule efficacy in DFNA9 patient-specific inner ear cells. 3)Delivery and biodistribution of ASOs in the mammalian cochlea and vestibular system 4)Safety and efficacy of DFNA9 ASO treatment in the mammalian inner ear. By using DFNA9 patient-specific stem cell-derived models, and our previously developed humanized DFNA9 mouse model, we can immediately investigate the ASO for future use in patients in all experimental paradigms. IMPACT: ASO-based treatments for dominantly-inherited HL are completely novel. The results obtained in this project are highly translatable and are likely to attract follow-up capital to swiftly translate our findings into the first treatments of DFNA9 patients. | 5.2 Cellular and gene therapies | 6project_grants_public
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gen_7d2a1877f19c68d5897e3b416f55241f | Assessing the impact of a new class of insecticide treated net (Interceptor G2) on malaria vectors population dynamics, ecology and behaviours in the Cascades Region of Burkina Faso. | Wellcome Trust | Centre National de Recherche et de Formation sur le Paludisme | HRCS22_14996 | Long-Lasting Insecticide-Treated Nets (ITNs) are the most successful method for malaria vector control in Africa. Growing evidence indicates changes in mosquito vector biting and resting behaviours in several African settings where high ITN coverage has been achieved. These combined with growing resistance to pyrethroids, the insecticide class used in all nets, can reduce intervention success. This is the case in Burkina Faso where high outdoor biting and pyrethroid resistance is reducing the efficacy of standard ITNs. In response to this Burkina Faso, adopted the newly developed ‘Next Generation Nets’ in its 2019 mass distribution campaign, becoming the first country to deploy Interceptor G2 (IG2), a net combining a pyrethroid with chlorfenapyr, an insecticide that should be effective against pyrethroid-resistant vectors. However, my initial results from laboratory and semi-field studies on mosquitoes from the Cascades Region of Burkina Faso indicate much lower moralities with IG2 nets than expected from earlier trials raising concerns that local vectors may have already developed resistance to this insecticide class. Combining field and laboratory works in the Cascades Region I will assess for chlorfenapyr-resistance, its potential mechanisms and the impact of IG2 on Anopheles gambiae s.l. demography, behaviours (resting and biting) and malaria transmission potential. | 3.2 Interventions to alter physical and biological environmental risks | 6project_grants_public
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gen_bb280b84b4581f47a92e54cf1b6c44d8 | Identification of genetic modifiers modulating the diseases severity of LMNA-CMD | Muscular Dystrophy UK | INSERM | HRCS22_15011 | LMNA gene mutations are responsible for a wide spectrum of disorders, the majority of which affecting striated muscles with dilated cardiomyopathy. They may be associated with variable severity of muscular dystrophy, i.e. LGMD1B (mild/late muscle phenotype), EDMD (strong/young muscle phenotype) and LMNA-CMD (severe/congenital onset of muscle phenotype). Analyses of clinical and genetic data collected in the UMD-LMNA mutation database (www.umd.be/LMNA/) that we set up led to the identification of few LMNA hot-spot mutations associated with different severity of the disease and highlighted a vast genetic and clinical heterogeneity among carriers of a similar LMNA mutation. Although digenism could explain part of this heterogeneity, involvement of modifier genes has also been suggested. LMNA encodes for 2 protein isoforms: lamin A and lamin C. They are intermediate filaments of the nucleus, mainly localized underneath the inner nuclear membrane but also dispersed in the nucleoplasm at low level. Analyses of EDMD and LMNA-CMD patient and mouse cells have revealed an increase in the nucleoplasmic lamin A/C specifically in LMNA-CMD. In the current project, we aim at identifying such modifiers using whole genome sequencing and/or RNA-sequencing in a large French family presenting with either isolated cardiac disease or EDMD with variable age at onset of myopathic symptoms (AOMS) (aim 1) and in a cohort of patients harbouring the same EDMD hot-spot mutation presenting with more severe, congenital phenotype than usually observed (aim 2). Finally, aim 3 will functionally validate the different variants that would be identified in aims 1 and 2 using patient cells. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_5fa220b2ea353cf097dcbea3f7878510 | Developing an Evidence Generation Platform for Therapeutics with a focus on Low and Middle Income Countries (LMICs) | Wellcome Trust | Coalition for Epidemic Preparedness Innovations | HRCS22_15015 | CEPI’s vision is “creating a world in which epidemics and pandemics are no longer a threat to humanity”. We were established with a mission to accelerate the development of vaccines, but we know that vaccines alone are not sufficient to achieve this vision. COVID-19 uncovered major gaps and opportunities in the therapeutics preparedness and response landscape, including: 1. A serious gap in end-to-end coordination 2. Fragility of upstream research efforts, including short-lived industry interest and insufficient access-friendly funding 3. Specific gaps along the value chain in: evidence generation, host-directed therapeutics, manufacturing scale-up, epidemic- and pandemic-ready policy and regulation, and advocacy for epidemic- and pandemic-specific procurement and country-readiness mechanisms We believe the global community would be well served by CEPI expanding into therapeutics. This would maximise the benefit for global health by utilising CEPI’s well-regarded existing infrastructure, governance and processes. We propose a step-wise entry into therapeutics, starting with areas where existing CEPI capabilities can provide significant value for Therapeutics: evidence generation. Building on these entry points, CEPI will develop a longer-term strategy for how CEPI can best advance therapeutics preparedness and response, and, in doing so, help create a world in which epidemics and pandemics are no longer a threat to humanity. | No Research Activity assigned | 3networking_collaborative
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gen_4334ed19bbb66a5512607303524240ac | Australian Early Psychosis Collaborative Consortium (AEPCC) Clinical Registry & Clinical Trial & Translation Network | Wellcome Trust | University of Melbourne | HRCS22_15018 | We propose to address two key areas of research enrichment and public engagement related to our current Wellcome funding (establishing an Australia-wide clinical registry and clinical trials and translation network for early psychosis, the Australian Early Psychosis Collaborative Consortium, AEPCC). The first is co-design a comprehensive and world leading infrastructure for the meaningful involvement of young people and carers with lived experience of psychosis to support the national network of research trials, including necessary training and support. Secondly, utilising this infrastructure for lived experience engagement we will co-design at least two community engagement projects aimed to increase community knowledge and research uptake in young people experiencing a first episode of a psychotic disorder. At the end of the activity we will have developed a co-designed approach of embedding and prioritising the lived experience of young people and carers in the projects that will be prioritised by the AEPCC. We will also have crystallised our ideas as to how and where people with lived experience would like to be involved in promotion and leadership of the AEPCC. Both these outcomes involve scoping training needs and delivering long-term training and support for young people and carers to perform their roles. By the end of the activity we will have achieved a truly collaborative approach within the network to embed the voice of young people and carers with lived experience or early psychosis that will be able to continue and evolve as the AEPCC continues beyond the initial Wellcome grant period. | No Research Activity assigned | 3networking_collaborative
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gen_356a0fa06c255cf2ed30fb7c7bb6ea91 | Interactive play: a strategy to improve nurturing care and movement behaviours for infants | Wellcome Trust | University of the Witwatersrand | HRCS22_15048 | The persistence of under- and over-nutrition, in conjunction with poor adherence to movement guidelines and lack of stimulation evident among South African children, is indicative of a generation being raised in an environment that is not conducive to optimum early childhood development. This perpetuates an intergenerational cycle of health inequality.Nurturing care is essential for early childhood development, and relies on responsive and sensitive interactions between caregivers and infants. Considering the importance of caregiver-infant interaction, as well as of infant movement behaviours, I hypothesise that encouraging interactive play could improve childhood growth and developmental through both the biological pathways linked to infant movement, and nurturing care pathways that promote attachment and emotional development.This study proposes to test this hypothesis by designing, implementing and testing the efficacy of an intervention that encourages interactive play during infancy. This study uses a novel objective assessments of interactive play, as well as rapid participant feedback tools and an adaptive intervention design to enhance behaviour change and therefore intervention adherence. | 3.1 Primary prevention interventions to modify behaviours or promote well-being | 6project_grants_public
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gen_b07f7b80e43b703f4e65e7f30e6254ad | Does household food biodiversity protect adults against malnutrition and favour the resilience of Shawi Indigenous households to climate change related events? | Wellcome Trust | Cayetano Heredia University | HRCS22_15093 | Undernutrition is a major consequence of climate change. Biodiversity could enhance climate change resilience of local food systems by improving human nutritional outcomes and providing healthy local food resources during/after climate-related risks. What is unclear, however, is how food biodiversity (FBD) is linked to human nutritional status. This study aims to answer that question by investigating impacts of FBD on the prevalence of malnutrition-related anemia in Shawi Indigenous adults aged 15 to 60 years old and assess the role of FBD on the resilience of Shawi to extreme floods in past five years. This will be achieved through two complementary studies. In the first study, Shawi people who have experienced recent floods will have FBD measured using questionnaires and 24-hour recall. Anemia will be assessed using a novel, non-invasive, image-based application alongside measuring blood hemoglobin. Given that seasonal changes could affect FBD, a cross sectional study with repeated measurements will be conducted to explore if the association between FBD and anemia is stable at different times of year. In the second study, community-based participatory approaches will be used with Shawi participants to investigate the role of FBD on responding to extreme floods Key words: nutrition, biodiversity, Amazonia, resilience, Indigenous people | 2.3 Psychological, social and economic factors | 6project_grants_public
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gen_d0abbb2ca61ad749be85e50c45d995c1 | Understanding the drivers of persistent malaria transmission in a region targeted for elimination in southern Mozambique | Wellcome Trust | Manhiça Health Research Centre | HRCS22_15109 | Mozambique aims to eliminate malaria in several low transmission zones between 2020-2025 by intensifying core malaria intervention measures including universal coverage with long-lasting insecticide-treated nets (LLINs) and indoor residual spraying (IRS). Successful efforts will also aid in the elimination efforts in neighboring South Africa and eSwatini (Fig. 1). Persistent residual transmission remains a major stumbling block for elimination. Yet, Mozambique is still the 6th highest in the number of malaria cases globally, indicating a much greater need to suppress transmission before we can consider elimination. Recent local surveillance indicates that both primary and multiple secondary malaria vector species are regularly collected. The role of secondary vectors in malaria transmission is understudied in Mozambique. Experimental hut and larval ecology studies conducted during my Ph.D., further corroborate the “ubiquity” of diverse Anopheles species present in Mozambique. Another challenge identified during my recent study in two districts in the region indicated that communities modify IRS sprayed surfaces post-spraying1. I hypothesize that shifts in vector and human behavior, secondary vectors, and increased spread of insecticide resistance are the major barriers to elimination. I will assess the persistent malaria transmission and its determinants, to inform a more effective future of vector control in the area. | 3.2 Interventions to alter physical and biological environmental risks | 6project_grants_public
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gen_3c72df62bf5fa3fbcff648801faffcac | AMR Newsletter and matching AMR.Solutions website | Wellcome Trust | Rex Life Sciences LLC | HRCS22_15129 | Starting February 2017, the insight from a significant amount of the Wellcome Trust-supported Expert-in-Residence work done by the applicant in support of the R&D efforts of the AMR community has been translated into a newsletter and a mirroring blogpost website. This content has come from attending key meetings (Dr. Rex is often asked to present, chair, and/or serve on program committees), authoring papers, and engagement (ad hoc email, TCs, and/or face-to-face meetings with key members of the developer community. Wellcome Trust supported this work 2017-2019 through hourly billing and expense reimbursement. It is now proposed this support be converted to a fixed-term grant with consideration of the possibility of extensions of the grant if / as the DRI program progresses The grant funds would be used to transformation and grow the project in 3 ways: 1. Website upgrade for improved analytics and visual quality. 2. Audience growth beyond R&D to the disciplines as finance, corporate leadership, and media relations, all of whom are key to success in this area. 3. Social media outreach by maintaining the core USP while making use of Twitter, Facebook, Instagram, and LinkedIn to reach more deeply into the audience of those working in antibiotic R&D. | No Research Activity assigned | 3networking_collaborative
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gen_bf78627a8e34756a3a729b32a4d16e88 | Risk variants and genetic architecture of ALS in sex- and population-specific subgroups | MND Association | Trinity College Dublin | HRCS22_15137 | Amyotrophic lateral sclerosis (ALS) is significantly heritable, but, despite considerable investment, remains enigmatic in its root causes for the majority of cases. Genomic studies of ALS such as genome-wide association studies have yielded relatively few definitively associated genetic loci and limited insight into the genetic architecture of the disease. A likely contributor to this is the restrictive models used in estimating the contribution of genetics to ALS risk. These models carry numerous assumptions that are violated in ALS, with imbalanced stratification of disease incidence between sexes and apparent non-uniformity of genetic determinants of disease across populations. Furthermore, most genomic studies in ALS have been restricted to the single phenotype of “classical” ALS, despite abundant evidence for causal or pleiotropic relationships between ALS and a number of other traits. Together, these assumptions restrict the extent to which ALS can be adequately explained from a genomic perspective and limit the biological insights that can be derived from genomic studies. The proposed research will, through collaboration with Prof. Jan Veldink at UMC Utrecht and the Project MinE Consortium, re-analyse the largest genomic datasets available for ALS, including genome-wide association study data for over 150,000 individuals and whole-genome sequence data for more than 10,000 individuals. This re-analysis will challenge these assumptions and genetically assess ALS risk from sex- and population-specific perspectives, as well as mapping out causal and non-causal genetic relationships with secondary neurological traits within these subgroups. Under a range of plausible models for which there is considerable support, this improves power to understand the genetic basis of ALS and its subtypes, which will be crucial for the future of patient categorisation in precision therapeutics and for disease prediction in unaffected individuals, as well as yielding novel insights into the biology of ALS and improving cellular and animal models of the disease. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_88269b1e3ed71f6f6ded7330d33853d0 | Role of LIN28B-mTOR axis in supporting cell plasticity and hair cell regeneration | Royal National Institute for Deaf People | Johns Hopkins University | HRCS22_15169 | The aim of the proposed study is to address whether re-activation of LIN28B-mTOR pathway allows for auditory hair cell regeneration in mammals. Loss of auditory hair cells due to disease or trauma is permanent and is the leading causes for hearing impairments and deafness in humans. Immature auditory supporting cells do regenerate hair cells in response to regenerative cues. However, such regenerative capacity sharply declines as supporting cells mature. We recently reported that the decline in supporting cell plasticity is linked to rising levels of let-7 miRNAs in supporting cells. The let-7 family of miRNAs are known inhibitors of cell proliferation, stemness and growth. Preliminary data suggest that overexpression of LIN28B, a mutual antagonist of let-7 miRNAs extends the window of supporting cell plasticity beyond the neonatal stage. Furthermore, preliminary studies suggest that LIN28B-enabled hair cell regeneration requires mTOR signalling. Based on these findings, we hypothesize that mature supporting cells fail to regenerate hair cells due to their inability to re-activate LIN28B-mTOR signaling. Furthermore, based on LIN28B’s positive role in cell reprogramming, we hypothesize that LIN28B-mTOR signaling facilitates hair cell regeneration by promoting supporting cell de-differentiation. Aim 1 will address whether LIN28B-mTOR activation in supporting cells induces a transitional progenitor-like state by examining LIN28B-mTOR induced changes in supporting cell-specific gene expression during hair cell regeneration. Aim 2 will examine whether the re-activation of LIN28B and or mTOR signalling enables mature supporting cells to proliferate and generate hair cells using a novel organoid culture system. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_edc86eef2bb9158f116b31e57cd9b80f | Development of ALS progNOstic biomarkers based on patterned neural network dysfunction | MND Association | Trinity College Dublin | HRCS22_15174 | Despite substantial heterogeneity of presentation and progression, ALS is currently managed as though it is a single neurodegenerative disorder. With the exception of gene based therapies, most clinical trial designs rely exclusively on clinical parameters to stratify patients into “fast” and “slow” progressors, and on clinical evaluation (ALS functional rating scale revised, ALSFRS-R) to determine progression and outcome. These parameters are limited in their ability to capture underlying disease heterogeneity, due to low sensitivity of the subscores, variability in the overall slope, and emphasis on motor aspects of disease while excluding NOn-motor components including cognitive and behavioural change (Rooney et al. 2017). By contrast, there is compelling emerging evidence that direct measurements of cortical and corticospinal network activity can provide objective and measures of early ALS pathology. For example, transcranial magnetic stimulation (TMS) which measures of upper motor neuron function and quantitative electroencephalography (EEG), which measures of cognitive network function, correlate with clinical findings and can presage future disease progression(Vucic et al. 2008; Poil et al. 2013; Dukic et al. 2019; McMackin et al. 2019b, 2020). Based on these observations and on my preliminary data, my hypothesis is that ALS subpheNOtypes differ with respect to patterns of cortical and corticospinal network dysfunction which may be captured by a combination of cortical EEG- and TMS-based measures and lower motor neurone EMG-based measures. I will record a battery of EEG, TMS and EMG measures longitudinally in a large cohort of ALS patients and correlate these measurements with indices of clinical and cognitive symptoms. I will cluster patients into subpheNOtypes based on a combination of measures which predict each individual’s concurrent and future symptoms. I will then test my hypothesis that changes in neuroelectric signal patterns alone can define subpheNOtypes with different clinical presentations and disease progression. | 4.1 Discovery and preclinical testing of markers and technologies | 6project_grants_public
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gen_ec8613bfa40f02973c49a9d5e527b411 | Chicken liver and eggshell crackers as a safe and affordable animal-source food for overcoming micronutrient deficits during pregnancy and lactation in Indonesia: a double-blind randomised controlled trial | Wellcome Trust | SEAMEO Regional Center for Food and Nutrition | HRCS22_15176 | A double-blind two-phase cluster randomized controlled trial will be conducted in West Java, Indonesia. Total 308 pregnant women will be recruited from 28 clusters (villages) in Sumedang district. Women who fulfil trial criteria will be randomly selected and invited into the trial. Clusters will be randomly assigned to receive placebo or micronutrient-enriched crackers (MEC) daily, distributed by cadres from 14 weeks to 5 months post-partum. Placebo and intervention crackers (recipe developed from chicken liver and eggshell by Food Scientists at University of Otago and pre-tested for acceptability) will be manufactured locally so they are identical in size, colour, and packaging, with a code known only by the local production manager who will not share the code until the primary outcome has been analysed statistically. Primary outcomes will be birth length and infant linear growth (attained and incremental). Secondary outcomes will be: (a) birth weight; (b) maternal haemoglobin at 37 weeks gestation; (c) volume and breastmilk micronutrient concentrations at 5 months post-partum; (d) maternal dietary intakes at 37 weeks and 5 months post-partum; (e) maternal micronutrient status at 37 weeks and 5 months post-partum; (f) micronutrient status of breastfeeding infants at aged 5 months. Analysis will be by intention to treat. | 6.1 Pharmaceuticals | 6project_grants_public
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gen_c294380658e78cb7e3db7af7811581f7 | Does neuromodulation have what it takes to silence tinnitus for the long-term? | Royal National Institute for Deaf People | Flinders University | HRCS22_15180 | It is estimated that 1 in 8 people in the UK suffer from chronic tinnitus. Currently, the most effective treatment strategies are psychological management approaches that reduce the distress caused by the tinnitus, but do not change the tinnitus itself, and to date there is no treatment that has a consistent and reliable long-term effect on tinnitus loudness or annoyance. Non-invasive neuromodulation approaches have been proposed as a means to directly influence tinnitus-generating neural networks in the brain. Transcranial direct current stimulation (tDCS) seems particularly promising, with reliable temporary suppression of tinnitus in study participants (up to 70%), and complete remission for up to three days in some cases. With high-definition (HD) tDCS, specific brain regions can be targeted, but the optimum stimulation regions and paradigms still need to be determined which can result in to long lasting impact on tinnitus. In this project, we will compare the effects of HD-tDCS of auditory cortex or prefrontal cortex or simultaneous stimulation of both brain areas, to determine the most effective stimulation paradigm for long-term tinnitus reduction (study 1). Additionally, we will use fMRI to investigate changes in tinnitus-generating networks in the brain through HD-tDCS (study 2), which will help us understand the mechanisms of tinnitus suppression in the brain. The data collected in this project will serve as pilot data to enable large-scale clinical trials of HD-tDCS for tinnitus management, which could then provide the evidence base required to establish HD-tDCS as a clinically viable management option for chronic tinnitus. | No Research Activity assigned | 6project_grants_public
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gen_f0fcee544948a17f51f81f1af258161f | CLIC5 functions in hearing and deafness | Royal National Institute for Deaf People | Indiana University | HRCS22_15185 | Mutations in CLIC5, which encodes a protein of undetermined function, cause hearing loss by unknown mechanisms. CLIC5 is concentrated at the basal taper region of stereocilia and interacts with taperin, which could modulate the actin cytoskeleton in cochlear hair cells. By performing comprehensive genetic, biochemical and histological analyses, the researchers will investigate whether CLIC5 could regulate taperin function/localization in hair cells and inhibiting taperin expression could restore the hearing in CLIC5-deficient mouse. In addition, an unbiased screening will be performed to determine interaction partners for CLIC5 that functionally cooperate during the development of hair cells. | 1.1 Normal biological development and functioning | 6project_grants_public
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gen_1ae23bf3ef0d77f55a6275dce06055d1 | Exploring mitochondria-to-nuclear communication in pancreatic cancer initiation | Worldwide Cancer Research | Venetian Institute of Molecular Medicine | HRCS22_15702 | Pancreatic cancer is characterized by poor overall survival and few efficacious therapeutic interventions. One area that has offered significant scope for further exploration are the numerous metabolic disturbances in preclinical models of pancreatic cancer. Several of these derangements lead to imbalances in metabolites, including S-adenosylmethionine (SAM), α-ketoglutarate (αKG), and acetyl-CoA that are crucial to the regulation of epigenetic landscapes. Previously, I have demonstrated that pancreatic cancer initiation features abundant epigenetic reprogramming in the progression to neoplasia, and that the cytoplasmic enzyme ATP citrate lyase, which produces acetyl-CoA from citrate, is essential to the neoplastic process. In mouse models, Acly deletion diminishes the enhancement of histone acetylation that occurs in response to mutant Kras. The role of mitochondrial generation of the ACLY substrate citrate in acetyl-CoA availability, and the downstream effect of mutant Kras-induced acetyl-CoA on chromatin landscapes both remain unknown. Our long-term goals are to identify how metabolic rewiring impacts the epigenome to facilitate alterations to cell fate in cancer. In this proposal, we intend to define the mitochondrial-to-nuclear connections that control epigenetic reprogramming in pancreatic cancer initiation. Building from my previous work, from Luca Scorrano’s expertise on mitochondrial dynamics, and from novel tools developed by Rohit Chandwani, our aim is to elucidate the mechanisms by which mitochondrial function controls the availability of exported citrate and nucleo-cytoplasmic acetyl-CoA. We will utilize several perturbations to citrate synthesis and export as well as to mitochondrial structure and function to delineate cross-talk between the mitochondria and the cytosol in controlling acetyl-CoA. The data from this study will be incorporated in a larger framework, where using an orthogonal approach, we will examine the global effect of alterations in acetyl-CoA abundance on the epigenome and preneoplastic cell fate in order to reveal mitochondrial control of acetyl-CoA as a therapeutic vulnerability in this otherwise deadly disease. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_523da40d5f6202bf97b56f0b157bbeaa | Digital Health Research Programme Year 2 | Cystic Fibrosis Trust | Cystic Fibrosis Canada | HRCS22_15718 | Use smart technologies to explore if it is possible for adults with CF to safely avoid the current routine CF clinic appointments when stable and provide more timely interventions to individuals based on the measurements taken at home. Use advanced analytical tools to interrogate existing UK CF Registry data to address key questions relevant to people with CF, in particular the very different disease progression trajectories for people with identical CF mutations and the differences in their responses to new disease-modifying drugs. Ultimately, the programmes of work will help move treatment of CF from Precision Medicine to one of Personalised Medicine: treatment and care tailored to the individual rather than the cohort average. | 4.2 Evaluation of markers and technologies | 6project_grants_public
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gen_77bf5807ff4c64e0de0516a6d53c8ff9 | Structural basis of B-cell Receptor-mediated cell-autonomous signalling in chronic lymphocytic leukaemia | Worldwide Cancer Research | Fondazione Centro San Raffaele | HRCS22_15720 | B cell receptor (BcR) signaling is a central event in the pathogenesis of chronic lymphocytic leukemia (CLL). Inhibitors of downstream effectors of BcR signaling display good clinical efficacy, yet have a limited capacity to induce profound clinical responses, and frequently lead to side effects due in part to off-target activity. Thus, the key challenge towards optimal CLL patient management remains the development of tailored treatments that target the BcR-mediated signaling, while taking into account the patient-specific modalities of receptor activation. CLL patients are heterogeneous in leukemic cell phenotype and clinical outcome, but can be grouped in subsets that present homogeneous clinicobiological features based on the expression of highly homologous BcRs. A unique feature of CLL B cells is their ability to signal autonomously in vitro, through homotypic recognition of the BcR. We recently showed that these BcR interactions are different and specific for each subgroup of patients as defined by the receptor structure. Here, we propose an integrated approach to characterize the structure and self-recognition of BcRs derived from the most common CLL subsets. First, we will determine the high-resolution crystal structures of BcRs from three common stereotyped subsets, as well as non-stereotyped IGHV1-69 receptors. Then, will use mutagenesis and biophysical methods to fully characterize and validate the homotypic binding of the receptors observed in the crystals, and to investigate existing correlations between BcR contacts and clinical course of disease. Finally, we will perform an in silico screening of chemical libraries to identify compounds antagonizing the autologous BcR interaction in the most common CLL cases, and test these in a reconstituted B cell system. The results of the research outlined will widen our knowledge on the mechanism leading to CLL onset, improve patients management, and provide lead compounds against a prevalent form of the disease. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_64c5afa2c2724265bde51231d9c1e17c | Local and Sustained Release of ChondroitinaseABC-37 to the Chronically-Injured Spinal Cord | Spinal Research | University of Toronto | HRCS22_15808 | Chondroitinase ABC (ChASE) is a potent enzyme that has repeatedly shown great promise in spinal cord injury; yet, its inherent instability and the few choices for sustained delivery have limited clinical translation. We invented a more stable and active form of ChASE, ChASE37, and a strategy for sustained local delivery based on affinity release (AR). We propose to take advantage of these inventions and test ChASE37-AR first in rats and then in dogs. Four weeks after a moderate spinal cord contusion model in the rat, we will test intraparenchymal vs. subarachnoid delivery of ChASE37-AR, using ultrasound to guide the injection. We will examine functional recovery prior to and post-treatment using an array of motor (Digigait, ladder walk, BBB) and sensory (pain) assays. Using chronic spinal cord injured rats, we will also compare our previously-designed methylcellulose-based delivery vehicle with a newly designed dextrin-based vehicle for biocompatibility, to ensure that we use the optimal vehicle and delivery strategy. We will be in a strong position to advance toward the clinic with continued guidance and engagement from our clinical co-PI, 2 patents on ChASE37 and the affinity release strategy, and behavioural improvements in rats. | 5.1 Pharmaceuticals | 6project_grants_public
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gen_be1f717e12a9debecd3a1e5236b46fae | Lassa fever near-patient PCR and haemostasis diagnostics | Wellcome Trust | University of Sierra Leone | HRCS22_15810 | Lassa fever is a life-threatening viral haemorrhagic fever and a major public health burden in West Africa, causing tens of thousands of cases annually with high patient mortality. The signs and symptoms of LF mimic common febrile illnesses in the early phase of the disease which makes diagnosis of the disease difficult. Severe disease is characterized by bleeding, the pathogenesis of which remains unexplained. Clinical patterns of bleeding and data from the 1980s have suggested that platelet dysfunction may be a major cause. This research project will study Lassa fever in adults and children in Sierra Leone. This project will develop and evaluate novel LASV assays in portable RT-qPCR systems to facilitate early diagnosis at the point of need, and will investigate the haemostatic changes in Lassa fever using modern assays, focusing especially on platelet dysfunction. We will assess whether thromboelastometry and coagulopathy biomarkers correlate with bleeding and disease severity. Flow cytometry will further improve understanding of the underlying mechanism(s) responsible for the coagulopathy. This research has the potential to achieve rapid impact, strengthen laboratory capability and provide new international academic collaboration in a neglected disease designated a priority for research by the World Health Organization. | 4.1 Discovery and preclinical testing of markers and technologies | 6project_grants_public
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gen_3f4b65f8408e2413bfa8a436b6ae5bea | Guidance on methodologies to measure the impact of vaccines on antimicrobial resistance (AMR) | Wellcome Trust | World Health Organization | HRCS22_15817 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public
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gen_02a46326f5f186f645cf8843ee7f7fe7 | Genetic dissection of factors contributing to disease severity in a fly brain tumour model | Worldwide Cancer Research | Foundation for Research and Technology Hellas | HRCS22_15818 | Since the discovery of oncogenes and tumour suppressors, it is known that a small number of genetic insults can transform healthy cells into precancerous. Decades later, we are still trying to fathom the multitude of additional defects that underlie full-blown malignancy. Model organism cancer models with carefully controlled genetic make-up are invaluable in achieving progress in this direction. In the past decade, a number of Drosophila cancer models were developed, that have helped understand aspects of carcinogenesis, such as multiclonality and metastasis. We are studying a cancer model from juvenile fly neural progenitors, which can be immortalized by serial allografting. We have performed transcriptome and histological analysis of this tumour, as well as two genetically defined variants, where we knocked down two key chromatin regulators, the NuRD nucleosome remodeling complex and the PRC2 histone methyltransferase. One of these variants grows more aggressively whereas the other is more benign. From analysis of differentially expressed genes, we have zeroed-in on a number of putative enhancers and suppressors of malignancy; these are the focus of the present proposal. Curiously, a cohort of 15 transcription factors, normally associated with early steps of neuronal differentiation, is upregulated in the more malignant NuRD-compromised variant. At the opposite end, activation of the Toll and JNK pathways is a hallmark of the less malignant PRC2-compromised variant. We propose to perform an in-depth in vivo study of tumours manipulated for these putative modulators in order to determine whether their upregulation causally underlies increased/suppressed malignancy or is simply a collateral effect. In parallel, we shall address the ability of these tumours to induce organ wasting to their hosts: this is more pronounced in the less aggressive tumour. We shall therefore scrutinize its secretome and use genetic manipulations to ask whether one or more tumour-produced cytokines are responsible for host cachexia. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_36e184fdf57f9b7b200b1facf1f8d943 | Analysis of somatic recombination in lymphoid cells to unravel DNA end joining regulation in cancer | Worldwide Cancer Research | Institut Pasteur | HRCS22_15819 | DNA double-strand breaks (DSBs) are toxic cellular lesions that must be efficiently repaired to maintain genome stability and prevent cancer. The two main DSB repair pathways are homologous recombination (HR) and nonhomologous end joining (NHEJ), with pathway choice partly determined by functional antagonism between the HR-promoting factor BRCA1 and NHEJ-promoting proteins, notably 53BP1/RIF1/MAD2L2. We recently identified two novel genes that encode for previously uncharacterized proteins termed shieldin (SHLD)1 and SHLD2 that form the shieldin complex, which we determined as being the downstream effector of 53BP1/RIF1/MAD2L2 in promoting NHEJ and antagonizing BRCA1-mediated HR. Importantly, loss of SHLD1 or SHLD2 renders poly(ADP-ribose) polymerase (PARP) inhibitors ineffective in BRCA1-deficient cancer cells. In addition, we have established that the shieldin complex plays major and distinct roles during antigen receptor gene diversification in lymphocytes, specifically RAG1/2-induced V(D)J recombination and AID-induced class switch recombination (CSR). In this research program, we propose to utilize programmed DNA recombination processes in lymphocytes to unravel the functions of the 53BP1-MAD2L2-shieldin axis in DSB repair. Specifically, we will analyze at the molecular level the impact of the loss of 53BP1, MAD2L2, and the shieldin complex on recombination intermediates and products. We will also test genetic and functional interactions between NHEJ and the 53BP1-MAD2L2-shieldin axis during V(D)J recombination and CSR. In addition, we will identify the local protein complexes associated with MAD2L2 and SHLD1 upon induction of programmed DSBs. Finally, we will use dedicated genetically modified mouse models to reveal the roles of SHLD1 and SHLD2 in lymphopoiesis. Ultimately, through these studies, we aim to discover novel modes of regulation of DSB response and repair that could contribute to the development of novel DNA repair based cancer therapies. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_226bfe1bfd64fab07c03bcc363453f9a | Smoke Free Partnership proposal for advocacy core funding 2020-2022 | Cancer Research UK | Smoke Free Partnership | HRCS22_15823 | The Smoke Free is an independent, flexible and dynamic organisation which coordinates European and national advocacy organisations working in tobacco control, and promotes collaboration in order to improve health and strengthen the voice of tobacco control and tobacco policy research at European and national level. SFP’s vision is a world where all children can grow up healthy, and free from the harm caused by tobacco. SFP co-ordinates a formal Coalition of organisations active in tobacco control across the WHO EURO region with the aim to promote and coordinate tobacco control advocacy on priority policy areas of the Framework convention on Tobacco control (FCTC). The Coalition currently consists of 45 organisations in EU member states and neighbouring countries. This proposal aims to support SFP's advocacy work in 2020-2022. European advocacy for tobacco control remains crucial to advancing implementation of the Framework Convention on Tobacco Control in Europe in particular with respect to taxation, the fight against illicit trade, policy oriented research, smoke-free policies, the introduction of plain standardized packaging, and the monitoring and strengthening of advertising laws. SFP will also work at European level to support global advocacy efforts for unlocking official development assistance (ODA) funding for the FCTC to help bridge the funding gap and implement the Global Strategy for Accelerating Tobacco Control. Finally, SFP will support capacity building and strategic policy campaigns by working with Coalition partners at eregional and national level. The SFP strategic objectives for the funding period are: 1. Develop multisectoral advocacy for the implementation of the FCTC at EU and national level in Europe as an effective way to prevent the morbidity and mortality from chronic diseases and cancer. 2. Develop and implement a European-level advocacy campaign to mobilise funding for global FCTC implementation in cooperation with FCA and advocacy partners in key European countries. 3. Maintain and strengthen SFP’s and the SFP Coalition’s advocacy capacity to meet its strategic objectives, including organising or attending relevant European and international tobacco control conferences. | 3.2 Interventions to alter physical and biological environmental risks | 3networking_collaborative
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gen_872ce9942af59d3057e9cd587adb7032 | ImmuNOlogy Project | Duchenne UK | University of Florida | HRCS22_15836 | This project is looking at immune responses to gene therapy | 5.2 Cellular and gene therapies | 6project_grants_public
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gen_bd7e074925d2515bf2b64196e759cc5d | Eradicating the minimal residual disease in melanoma | Worldwide Cancer Research | Vlaams Instituut voor Biotechnologie | HRCS22_15847 | Inhibitors of MAPK signalling have led to unprecedented clinical responses in patients with BRAF-mutant metastatic melanoma. However, the clinical benefit of such agents is limited by genetic alterations that occur (by chance) before or during the treatment, leading to intrinsic or acquired resistance respectively. Additionally, cancer cells can escape the effects of targeted therapy through non-genetic adaptive mechanisms. This is the result of the ability of cancer cells to reversibly switch between drug sensitive, tolerant or resistant phenotypes, owing to cellular plasticity. These clinical observations have highlighted the need for combinations and/or sequential therapies that contend with this “chameleonic” behaviour of cancer cells. Using single-cell sequencing we find that minimal residual disease (MRD) in melanoma is composed of drug-tolerant populations of persister cells that can harbour both differentiated and de-differentiated phenotypic features. Using trajectory analysis pipelines, we reconstructed the transcriptional dynamic time course and lineage relationships and find that the persister cells are distributed along pseudo-temporally ordering paths with a population of "starved" melanoma cells (or SMCs) that is present at the branching point, preceding both differentiated and de-differentiated end states. These data indicate that drug exposure promotes a rapid and transient switch into a SMC state before persister cells make the decision to move along either a stable differentiation or de-differentiation trajectory. We propose herein to test the hypothesis that transitioning through this SMC state is an early adaptation and critical step for the emergence of both end states and that therapeutic strategies that target these cells will eradicate drug tolerance and, thereby, prevent the acquisition of resistance in a large fraction of melanoma. We will expose SMC vulnerabilities that are amenable to therapeutic intervention using cellular models and test the therapeutic potential of targeting SMCs in the context of rationally designed MRD-directed combination therapies using well-validated pre-clinical models. | 5.1 Pharmaceuticals | 6project_grants_public
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gen_60198f8fc0cb08342e546da176afe45b | Innovative aptamer-based approaches to specifically target DNA methylation in non-small-cell lung cancer | Worldwide Cancer Research | National Research Council | HRCS22_15859 | The development of effective therapeutics has become an unmet need to reduce non-small-cell lung cancer (NSCLC) patient’s mortality. DNA methylation is a key epigenetic modification regulating gene expression and its alteration is the most common molecular lesion in several cancers, including NSCLC. It thus offers an innovative therapeutic target to reprogram cancer malignant transformation. However, medical intervention has been limited to toxic, unspecific demethylating drugs. To overcome these limits, we addressed DNA methylation targeting by exploring nucleic acid aptamers, promising ligands with high affinity and specificity. We developed nuclease-resistant RNA aptamers able to bind and neutralize the major epigenetic player DNA methyltransferase (DNMT)1. In this project, we aim to demonstrate the therapeutic potential of these aptamers and develop effective, safe and clinically translatable approaches combining aptamers and theranostic nanovectors (tNVs) for NSCLC selective therapy. To this end, we will characterize the anti-DNMT1 aptamers (WP1) and design the optimal systems for their delivery evaluating two approaches: i) bispecific molecules containing anti-DNMT1 and NSCLC targeting aptamers (WP2); ii) tNVs loaded with anti-DNMT1 aptamers and decorated with a NSCLC targeting aptamer (WP3). For NSCLC targeting, we will use our previously described GL21.T aptamer that binds and inhibits the NSCLC-expressed Axl receptor. Systems will be validated in 3D organoids (WP4). This project will generate innovative demethylating agents and safe tools to deliver them to NSCLC, providing a paradigm shift in current therapies. In addition, it will afford important understanding of DNA methylation in NSCLC that can be exploited for other studies. Obtained results will permit the subsequent in vivo experimentation of our systems and their application to other types of cancers involving aberrant methylation. In the long-term, our technology may be implemented to increase the life expectancy and quality of NSCLC patients, thus representing an important milestone with great scientific and medical impact. | 5.1 Pharmaceuticals | 6project_grants_public
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gen_e5d1701eb09be5fb118afc4446962f43 | Using crowdsourcing to identify, characterize and target swarms of Anopheles funestus mosquitoes in rural Tanzania | Wellcome Trust | Ifakara Health Institute | HRCS22_15897 | Malaria burden in Tanzania has significantly declined following scale-up of long-lasting insecticide treated nets (LLINs)6. In some areas such as rural south-eastern Tanzania, Anopheles gambiae s.s, which was previously the number one vector has also disappeared under the intervention pressures. Unfortunately, a different vector species, An. funestus persists and now mediate >85% of ongoing malaria transmission despite their low densities2. These mosquitoes are also resistant to pyrethroids used on LLINs2,7, and require alternative control strategies. Greater understanding of ecology of An. funestus will offer additional opportunities to achieve malaria elimination8. Swarming and mating behaviours, though often neglected, are particularly crucial. For the first time in Tanzania, our research has recently revealed that An. funestus (and Anopheles arabiensis) mate in swarms, which occur repeatedly in same locations and same time each day3,5. Targeting these behaviours may provide new opportunities to crash vector populations and drastically reduce malaria in areas where LLINs have achieved significant reductions but low-level transmission persists. Indeed, studies in Burkina-Faso have provided evidence that targeting swarms can reduce vector population by 80%9. I propose to demonstrate that An. funestus swarms can be identified, characterized and targeted for control with help from trained community members in selected Tanzanian villages. | 2.2 Factors relating to physical environment | 6project_grants_public
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gen_344fd6a1c846074bcdaa0f25efbb5938 | Characterizing the role of regulatory T (Treg) cells in the progression of aggressive mesenchymal-type colorectal cancer | Worldwide Cancer Research | University Medical Center Utrecht | HRCS22_15915 | Colorectal cancer (CRC) is one of the most common types of cancer in the Western world and the second most common cause of cancer-related mortality. Analysis of recurrent patterns of gene expression in CRC has led to the identification of four Consensus Molecular Subtypes (CMS1-4). Of all newly diagnosed CRC cases in the world (1.5 million worldwide), approximately 25% are CMS4 (375,000 new cases each year). CMS4, also known as the ‘mesenchymal subtype’, is characterized by high stromal content and high level TGFß signaling, an increased likelihood of distant metastases, and resistance to chemotherapy and EGFR-targeted therapy. Of all CRC-related deaths worldwide (700,000 per year) approximately 40% is estimated to be due to CMS4 (280,000). Arguably, the development of subtype-targeted therapy is most urgent for CMS4 CRC. We have recently found that CMS4 is characterized by a specific gene signature reflecting infiltration of regulatory T (TREG) cells and have found that mesenchymal-type CRC tumor organoids induce a dramatic increase in TREG cell numbers. This suggests that tumor cells may directly promote TREG cell expansion in CMS4, potentially contributing to local suppression of anti-tumor immunity. Here, a novel in vitro 3D CMS4 tumor organoid-TREG cell co-culture model will be used to determine the capacity of tumor cells to modulate TREG cell development, identity, expansion and phenotype. In parallel, novel in vivo mouse models for CMS4-like metastatic CRC will be utilized to further investigate TREG cell biology, and study the effect of TREG depletion on tumor growth and spontaneous metastasis formation. The enrichment of TREG cells in CMS4 CRC suggests that TREG -targeting therapy may be particularly effective against this subtype. However, more insight into TREG accumulation in CMS4 CRC, their function, and their role in metastasis and therapy resistance needs to be gained, before considering them as valid targets for therapy. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_aa62356b940a5017ecbef97f6f71f0d9 | Determining the effects of pediatric vaccination status on the burden of antimicrobial-resistant commensal organisms in a Guatemalan community | Wellcome Trust | Washington State University | HRCS22_15937 | We are initiating a CDC-funded study of antimicrobial-resistant bacteria in the western highlands of Guatemala. This study is in collaboration with investigators at Washington State University (WSU, USA), University de Valle de Guatemala (UVG), the Guatemalan Ministry of Health and Social Assistance (MSPAS), and the Central America Regional Office of the Centers for Disease Control and Prevention. The goal of this two-stage randomized, cross-sectional study (n=577 households) is (1) to estimate the prevalence of three groups of antimicrobial-resistant bacteria and Group A Streptococcus at the community-level, and (2) to identify risk factors for carriage of the target organisms including antibiotic use and hygiene variables. If funded, the current proposal will add 326 households (with participants <15 years old) to increase the power to detect a 27.3% vaccination-attributable reduction in the prevalence of extended-spectrum cephalosporin-resistant Enterobacteriaceae. All vaccinations will be considered, but with the proposed design we hypothesize that we will detect a statistically significant vaccine effect relative to rotavirus and-or pneumococcal vaccinations. Findings from this study will inform the MSPAS vaccination efforts and will be shared with the local, national and international communities (e.g., PAHO and WHO). | No Research Activity assigned | 6project_grants_public
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gen_96461c188c1a0244749f711917598c1f | Effectiveness of vaccines to prevent antibiotic prescribing for acute respiratory tract infections in high risk adults | Wellcome Trust | UNSW Australia | HRCS22_15956 | In high income countries the greatest use of antibiotics is in community (primary care) settings in the context of acute respiratory tract infections. Within these settings, both the very young, the very old and those with respiratory conditions such as asthma and chronic obstructive pulmonary disease are known to be the greatest antibiotic users. While there are a number of vaccines routinely provided that protect against acute respiratory tract infections, there is limited empirical data quantifying the potential benefit of vaccines to reduce antibiotic use for respiratory tract infections, particularly in adult populations. In this project we will use a large-scale database of electronic general practice records to quantify, in older adults, the effectiveness of influenza, pertussis and pneumococcal vaccines in reducing primary care presentations for acute respiratory tract infections and subsequent antibiotic prescribing. We will focus on high risk groups defined by age and/or co-morbidity (asthma and chronic obstructive pulmonary disease). We will use these estimates of vaccine effectiveness to model the absolute reductions in antibiotic use that could be obtained by increasing vaccine coverage in different adult sub-groups. This evidence will enable policymakers to better prioritise strategies to increase uptake of these vaccines. | 7.3 Management and decision making | 6project_grants_public
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gen_7b966e822bb74ccfcb4ef3c9b4c6c56c | Targeting the innate immune system to fight glioblastoma | The Brain Tumour Charity | Mass General Brigham | HRCS22_15959 | No abstract available for this analysis. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_ca017a35b62e2fd0cd664442e2e8abef | Strategies to optimize use of MDM2 inhibitors in glioblastoma multiforme | The Brain Tumour Charity | Dana Farber Cancer Institute | HRCS22_15960 | No abstract available for this analysis. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_7aed67abb06d5b0079825ef6f464d9eb | Targeting astrogliosis to ablate post-treatment tumour recurrence | The Brain Tumour Charity | University Hospital of Lausanne | HRCS22_15961 | No abstract available for this analysis. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_e987771e87df5ff696b4debead2c39a1 | Understanding how clonal hematopoiesis feeds lymphoma | Worldwide Cancer Research | Institute of Oncology Research | HRCS22_15962 | As the fifth most frequently occurring cancer type in humans, lymphoma still requires to be mechanistically better understood in order to achieve a satisfactory relative survival. A promising approach to close this knowledge gap concerning lymphoma consists in investigating the microenvironment and potentially occurring inflammatory processes, which may have a supportive effect on the emerging and maintenance of tumor progression. Clonal hematopoiesis (CH) is the accumulation of mutations in the myeloid-monocyte lineage in healthy individuals. CH has been correlated with inflammation and aging of immune response. One of the most-common mutations in CH is loss-of-function alleles in TET2. TET2 encodes an enzyme involved in epigenetic regulation of hematopoietic cells. Our working hypothesis is that TET2 mutated CH creates an inflamed niche of myeloid cells that support the tumor and/or impair the anti-tumor immune response. Our working hypothesis will be addressed through distinct tasks: 1.) Provide experimental proof that TET2 mutated myeloid cells are enriched in the intra-tumoral microenvironment of lymphoma patients with CH, and that they have a pro-inflammatory/tumor supportive phenotype; 2.) Validating that Tet2–deficient hemopoiesis promotes lymphoma development and 3.) Proofing that TET2 mutated CH is an unfavorable prognostic biomarker in lymphoma. The project leverage state-of-the-art and novel single cell technologies, novel strains of genetically modified mouse models of lymphoma, and clinical trial cohorts. The project will impact on our understanding of lymphoma biology and will create a new platform for therapeutic advances in this tumor. In terms of knowledge, we will discover a completely new and actionable mechanism of lymphoma promotion that may be termed as “monoclonal immune microenvironment” that will advance the understanding of the interplay between immune-aging and tumor development. In terms of treatment, we will generate both reagents and candidate targets from pre-clinical studies aiming at re-educating or eradicating the “monoclonal immune microenvironment”. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_de1a6783eba71dee9b3619f6076e1feb | Early exposure to radio-frequency electromagnetic fields and cancer: complete evaluation of the Ramazzini Institute long-term carcinogenicity bioassays on Sprague-Dawley rats | Children with Cancer UK | Istituto Ramazzini | HRCS22_15966 | Humans in modern society are exposed to an ever-increasing number of radiofrequency electromagnetic fields (RFR). Key sources of RFR include mobile phones, wireless networks and base station antenna. Concern is expressed about possible health effects, particularly children appears to be more sensitive to RFR than adults due to their developing system. In 2011, the International Agency for Research on Cancer (IARC) classified RFR as “possibly carcinogenic” to humans (group 2B) based on epidemiological evidence of a positive association between exposure to RFR and nervous system tumours. In the meantime, both the National Toxicology Program (NTP) and the Ramazzini Institute (RI) had already started a program to perform experimental studies on the health effects of RFR on rodents. The RI partial findings on far field exposure to RFR are consistent with and reinforce the results of the NTP study on near field exposure, as both reported an increase in the incidence of tumours of the brain and heart in RFR-exposed rats starting from prenatal life. Another carcinogenicity bioassay had been also performed by the RI to test the potential syn-carcinogenic effects of RFR in combination with gamma radiation. Up to now, the in vivo phase of both the RI ‘studies has been concluded and processing of tissues is still ongoing. In the present project, we aim to complete the histopathological evaluation of all the other tissues in order to provide sufficient evidence in experimental animals to call for the re-evaluation of IARC conclusions regarding the carcinogenic potential of RFR in humans. | No Research Activity assigned | 6project_grants_public
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gen_32649fa9a27b236ed545112a763deac1 | Biomarkers Part 2 | Duchenne UK | Duke University | HRCS22_15982 | This project will be looking at biomarkers to be used in clinical trials. | 4.1 Discovery and preclinical testing of markers and technologies | 6project_grants_public
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gen_216a3d785370cc502f5b1dd798bb4c0f | Exploring the functional role of EZH2-dependent autocrine signaling in T-cell leukemia | Worldwide Cancer Research | Casa Sollievo della Sofferenza | HRCS22_15987 | BACKGROUND: T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) is a malignancy with refractory/relapsed cases, presumably due to the ineffective targeting of leukemia initiating cells (LICs). DNA mutations, leading to the hyperactivation of Notch1 signaling, are found in >50% of human T-ALL. NOTCH1 binding induces the eviction of PRC2, which promotes the repressive H3K27me3 chromatin modification. Moreover, we observed that in NOTCH1-induced mouse T-cell leukemias, the shRNA-mediated knockdown of EZH2 (a functional component of PRC2) stimulates cell growth/survival by inducing an autocrine IGF-like signaling, critical for LIC activity. OBJECTIVE/HYPOTHESIS: This proposal intends to characterize the functional role of EZH2 in the NOTCH1-driven malignant transformation of human cells and to define the EZH2-dependent autocrine signaling involved in T-ALL pathogenesis. We hypothesize that the silencing of EZH2 modulates functional pathways of T-cell transformation and LIC activity underlying the different outcomes of relapsed/recurrent leukemias. SPECIFIC AIMS: Determine whether the loss of EZH2 promotes the malignant transformation of hematopoietic stem/progenitors(HSPCs) from human cord blood; Characterize the EZH2-dependent autocrine signaling in human NOTCH1-induced HSPCs; Define the functional role of EZH2 in the LIC activity of human T-ALL. STUDY DESIGN: We propose to use novel models of human T-ALL in which HSPCs from cord blood are transformed into clonal T-ALL-like malignant cells, after transduction with lentiviral vectors encoding NOTCH1-ΔE (a constitutively active NOTCH1 variant) alone or in combination with three known T-ALL oncogenes, and subsequent injection into immunocompromised mice. We will perform gain/loss-of-function assays to assess the EZH2 contribution to leukemogenesis and LIC-related phenotypes. We will employ ELISA/Luminex analyses, combined with RNA-Seq, ChIP-Seq and TaqMan gene expression assays for characterizing the EZH2-dependent autocrine signaling. Conventional EZH2 inhibitors and patient-derived xenograft(PDX) leukemias will be also included. SIGNIFICANCE: This study will outline relevant pathways of leukemia maintenance, development and chemoresistance and provide rationale for drug design by identifying novel molecular targets. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_16b481bae3b4d32be7991bc0d4bf5082 | AMR.Solutions newsletter, website, and connected social media | Wellcome Trust | Rex Life Sciences LLC | HRCS22_15992 | Since 2015, Dr. John H. Rex has worked to develop a digital communication platform for the antimicrobial resistance (AMR) R&D community both promotes innovative R&D and energizes policy changes to address the intertwined issues of access, stewardship, and innovation. The platform consists of a free newsletter, copies of each newsletter posted on http://amr.solutions and LinkedIn, tweets regarding newsletters, and a YouTube channel providing content related to the newsletters. As of this writing (May 2022), AMR.Solutions has 2,600+ subscribers from 50+ countries around the globe with an average of 2,500 opens and 800 clicks per newsletter. These subscribers are all heavily involved with AMR-focused projects and the newsletter is viewed as a must-read by many in the community. From a recent survey: “It provides information as well as analysis which are crucial to our thinking when tackling AMR. I am delighted that it has a wide range of topics covered from basic R&D to public health and policy.” A grant from Wellcome Trust for Sep 2020 to March 2022 provided transformative supportive for the project. This grant application proposes that Wellcome Trust again support the further transformation and growth of this project via website maintenance, audience growth, and digital presence. | No Research Activity assigned | 3networking_collaborative
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gen_f54ec7d406a1b5bf92bb518f137478a7 | Targeting GH signalling: a novel radiosensitising strategy | Worldwide Cancer Research | University of Auckland | HRCS22_15993 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public
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gen_efac2d3960b02e7f52d7cfe480d2672c | Role of PI3K-C2G in pancreatic cancer metabolism | Worldwide Cancer Research | University of Turin | HRCS22_15995 | Pancreatic cancer (PC) is the most lethal cancer across the world, with incidence equaling mortality. Recently, PC emerged as a metabolic outlier characterized by several metabolic dependencies, representing an unmet opportunity for the development of novel therapeutic approaches. A wealth of studies report that enhanced activation of PI3K/mTOR pathway has a critical role in the pathogenesis of PC and it is required for sustaining malignant growth and metabolism rewiring. The mTOR Complex 1 (mTORC1) is a key regulator of metabolic adaptation to nutrient availability, promoting anabolic pathways. Recently, it has been reported that PI(3,4)P2, a class II PI3K signaling product, can act as a local repressor of the mTORC1 signaling. Differently from other class II members which are ubiquitous, In particular, the PI3K-C2γ isoform is mainly expressed in the pancreatic tissue where it plays a pivotal role in cell metabolism. In human PDAC, the PIK3C2G gene is homozygous-deleted in about 7% of patients. Therefore, we decided to model PI3K-C2γ loss (PIK3C2G gene KO) in a mouse model of PC (KPC). We found that lack of PI3K-Cϒ increases tumor development and progression, strongly reducing mice mean survival rate and driving rapid progression to cancer. Biochemical analyses of PIK3C2G-deficient tumors revealed a specific hyperactivation of mTORC1 pathway, increasing metabolic alterations. To consolidate these findings, we aim at: i) assessing the oncogenic potential of PI3K-C2ϒ ii) dissecting PI3K-C2ϒ signaling pathway iii) exploiting metabolic dependencies of PI3K-C2ϒ loss iv) defining the prognostic and predictive value of PI3K-C2ϒ in PDAC. With this project, we expect to validate PI3K-C2ϒ as a novel tumor suppressor in PC and to establish a new mechanism by which PI3K-C2ϒ controls metabolic alterations induced by mTORC1 hyperactivation. Eventually, data obtained from this study will validate selective inhibition of critical metabolic pathways in PI3K-C2ϒ-deficient tumors to maximize therapeutic success. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_717cf461daf5404dbd6e59f3c727f716 | NUMB splicing modulation with AONs as a novel lung cancer treatment | Worldwide Cancer Research | Centre for Genomic Regulation | HRCS22_15997 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public
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gen_29b67c9117ecbf97c79e003bcb62a1f8 | Identifying key amino acid metabolic steps as potential drug targets for Chagas disease treatment | Wellcome Trust | University of Sao Paulo | HRCS22_16008 | Trypanosoma cruzi, the causal agent of Chagas disease, has a complex digenetic life cycle. This organism is well adapted to handle environmental changes, presenting high metabolic flexibility. In this context, amino acids and their metabolism play crucial roles in cell differentiation, maintenance of cell volume and response to different types of stress. This proposal aims to identify the key steps of the amino acid metabolic network which are crucial for T. cruzi to complete its life cycle. With this purpose, we will use the bar-seq CRISPR-Cas9 genome editing strategy to generate mutant knockout cell lines for the coding sequences of 40 enzymes putatively involved in the metabolism of amino acids. Each cell line will be identified by a unique sequence barcode and they will be pooled to allow parallel phenotyping during cell differentiation and infection, both in vitro and in vivo. Relative fitness will be assessed by next-generation DNA sequencing. Identification of the enzymes that are essential for parasite development and infectivity will provide insights on the metabolic strategies T. cruzi evolved to adapt to diverse environments as well as novel targets for target-specific drug design and ligand structure-based screenings in the future. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_0c93fb3636de6edfdd63ec36359fbcd6 | Research Enrichment Funding for the Public engagement programme of CIDRI-Africa | Wellcome Trust | University of Cape Town | HRCS22_16027 | The Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) at the University of Cape Town leads research programmes on high-burden infectious diseases, particularly HIV and tuberculosis. Through this enrichment grant, we will develop our researcher community as public engagement champions, improve our research through inolvement of our local communities and stakeholders, and raise awareness of our research to maximise health outcomes. To develop our researcher community’s involvement in PE, we will create and implement a PE communication toolkit, which will become an embedded component of study conduct at CIDRI-Africa, and enable our researchers to confidently engage the wider public. We will continue to engage the community with whom we conduct research through health research awareness activities, and establish a community advocacy programme to extend the work of CIDRI-Africa’s Community Advisory Group. Members of the advocacy programme will bridge research and non-research communities, providing input to both and effectively advocating tuberculosis and HIV research. We will engage young people through our school’s engagement project, drawing on methods from a previous pilot. This will follow a workshop format, and improve understanding amongst school learners and the people they connect with of tuberculosis and HIV as well as research into these conditions. | 7.1 Individual care needs | 6project_grants_public
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gen_60ff6246b8b55ab2fd56a82a1c02d80f | Decoding the role of lipids in the metabolic control of CD8+ T cells by the gut microbiota to improve outcomes in colorectal cancer. | Worldwide Cancer Research | European Institute of Oncology | HRCS22_16034 | Over a third of resected early-stage colorectal cancer (CRC) relapse and patients die from metastatic disease. Infiltrating lymphocytes are independent positive predictor of survival in CRC, however only a small fraction of patients respond to immune checkpoint inhibitors (ICI). This project originates from two milestone discoveries. First, the gut microbiome modulates response to ICI, but the overlap across different cohorts is mostly functional rather than compositional. Second, accumulation of specific lipids in the tumor microenvironment (TME) impact the anti-tumor activity of CD8+ T cells. We have conducted comprehensive metagenomic, metabolomic and immune characterization on CRC patients, observing parallel changes in mucosa and tissues. Thus, we hypothesize that therapeutic manipulation of the metabolic output of mucosal bacteria can reshape the TME and improve the response of CRC to ICI. This prospective study is designed to: . DECODE the interplay between metabolic activities in the intestinal mucosa and immune cell functions on CRC patients; . VALIDATE the effect of lipids derived or induced by bacteria on immune cell functions; . TRANSLATE new knowledge into innovative strategies to improve ICI efficacy. Main objectives are: . Quantification of lipids and reconstruction of bacteria-host metabolic pathways, in tumours and surrounding tissues; . Characterization of the immunomodulatory impact of the microbiota on CD8+ T cells; . Mechanistic validation and improvement of ICI’s response on a novel patient-derived organ-on-chip device. This study will enable multi-scale profiling and predictive modelling on a fully annotated cohort while simultaneously spawning novel actionable targets for therapy. Tumour sensitivity to ICI will be tested, providing initial experimental validation on a patient-relevant and cost-effective system. Data generated through this project may also reconcile the limited association between the overall composition of the microbiome and the response to immunotherapy across different cohorts of patients, a crucial step toward new stratification strategies and therapeutic approaches. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_71360dbc15ca1d51bf69d731fa5a8b61 | Dissecting the molecular mechanisms that sustain frequent oncogenic BAP1 mutations | Worldwide Cancer Research | European Institute of Oncology | HRCS22_16035 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public
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gen_2cacb7896490467096a363147d172390 | Investigating the roles of NF-κB subunits as master regulators of CD8+ T-cell function in cancer immunity and immunotherapy. | Worldwide Cancer Research | Cancer Center of Lyon | HRCS22_16036 | Cancer progression is greatly influenced by a delicate balance between tolerance to and immune response against tumors. The recent success of immunotherapies such as checkpoint-blockade therapies, demonstrates that this balance can be shifted effectively towards enhanced anti-tumor immunity, to delay or even stop cancer progression, particularly by enhancing the function of CD8+ T cells. However, only a fraction a patients respond to these regimens, and the molecular mechanisms that drive the response and resistance to immunotherapies are largely unknown. The transcription factor NF-kappaB (NF-kB) has been implicated in the regulation of T-cell function. However NF-kB is in fact a family of transcription factors composed of 5 distinct subunits; due to the lack of suitable tools, the contribution of individual subunits of NF-kB to CD8+ T-cell biology has never been addressed. In this application, we propose to investigate the exact roles of NF-kB subunits that control CD8+ T-cell function in cancer immunity. We will use unique mouse models carrying ablation of NF-kB subunits specifically in mature CD8+ T cells, CRISPR-based gene edition in primary human cells and high-throughput sequencing analyses. Based on our previous publications and preliminary data, we hypothesize that the activation of selective NF-kB subunits orchestrates CD8+ T-cell biology and underlies the clinical response to checkpoint-blockade therapies. Importantly, these studies may reveal specific NF-kB subunit activities that can be targeted by novel therapeutics to enhance T-cell function alone or in concert with existing immunotherapies. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_431da97927d45c6519c56d8db25052f7 | Identifying properties of tumour suppressive pericytes for cancer therapy (PERISUPPRESS) | Worldwide Cancer Research | CERCA Institution | HRCS22_16064 | Non-transformed co-habitant cells, defined as stroma, play key roles in the development and progression of tumours. Thus, understanding their function is instrumental for the efficacious eradication of the disease. Taking advantage of computational analyses, a unique collection of prostate cancer (PCa) mouse models, and our know-how expertise in pericyte biology, we have identified that pericytes inform about PCa recurrence and metastasis. Here, we postulate that the study of molecular cues governing the pericyte-cancer cell relationship provides an innovative perspective of the aggressive properties of cancer cells. This may serve to define therapeutic strategies that would be missed in a classical tumour cell-centred discovery approach. PERISUPRESS aims to identify the molecular and cellular mechanisms which promote tumour suppressive properties in pericytes by: (1) a discovery approach to identify pericyte-related molecular cues associated with PCa progression; (2) the study of the impact of pericyte-specific molecular programs on PCa progression; (3) the identification of pericyte-related vulnerabilities associated to PCa progression. This will be done through awell-balanced experimental plan which includes mouse models and patient-derived samples from PCa at different disease grades, computational biology and multiple in vitro and in vivo functional and mechanistic approaches. In summary, the study of pericyte biology in PCa has the potential to open a new window in the comprehension and treatment of aggressive PCa that may also be applied to other types of cancer. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_00c124ae962579836cb4cb0bb2f9d026 | ‘We are the heroin capital of Europe’: Marginal Communities, Health, Identity, and the Opioid Epidemic in Twentieth-Century Ireland | Wellcome Trust | University College Dublin | HRCS22_16079 | Keywords: Heroin, drugs, Ireland. By 1990 heroin had devastated working-class communities across Dublin and, in some families, wiped out entire generations. But how did things reach that stage when three decades previously heroin was only known in Ireland as a symbol of distant, undesirable, foreignness? This project will explore the history of heroin in Ireland, from its first public discussion (1918) to the end of the first heroin epidemic (1990). It will approach the history from two directions. First, analysing the public discourse about the drug. This will reveal, inter alia, different ways that heroin was used as a symbol of dissolute otherness, and how this shaped health policy and provision. Secondly the project will collect 100 oral histories to investigate how heroin affected everyday life in the communities at the centre of the heroin epidemic of the 1970s and 1980s. Finally, the project will use reception theory to integrate these approaches and achieve three key goals: • To understand how the public discourse shaped community members’ interaction with each other, the wider world, and healthcare providers. • To give marginalised communities a voice in the production of their own history. • To produce the first history of heroin-use in Ireland. | 8.1 Organisation and delivery of services | 6project_grants_public
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gen_66f98f411b2deb166b213db3216ce699 | Unravelling the requirement of Rad18 in glioblastoma proliferation | Worldwide Cancer Research | Cancer Research Center of Toulouse | HRCS22_16094 | Glioblastoma is the most frequent and aggressive primary brain tumor characterized by a strong resistance to therapy involving treatment with ionizing radiations and alkylating agents. The molecular grounds of this acquired resistance are currently unknown. The identification of novel therapeutic targets constitutes therefore a priority. We and others have recently reported an implication of the Rad18 (E3) ubiquitin ligase in the resistance of glioblastoma to cisplatin and ionizing radiations. Rad18, a critical component of DNA damage bypass, activates translesion synthesis by catalyzing the transfer of an ubiquitin monomer on PCNA, a well-known proliferation-associated antigen. This results in recruitment of translesion synthesis DNA polymerases to allow DNA synthesis through DNA lesions thus facilitating escape of apoptosis and contributing in resistance to therapy. In addition, Rad18 is also implicated in repair of single and double DNA strand breaks as those generated by the radiotherapy. Unexpectedly, by analyzing the phenotypes associated with Rad18 downregulation in glioblastoma, we have observed that Rad18, which is non-essential for life, is essential for the proliferation of glioblastoma cells, and in particular of glioblastoma cancer stem cells (GCSCs), those cells currently strongly implicated in the resistance to the therapy. The aim of this work is to unveil the specific function of Rad18 in the proliferation of GCSCs and to propose Rad18 as novel therapeutic target in the treatment of glioblastoma. This will be achieved thought the identification of the molecular pathway(s) in which Rad18 is implicated through genome-wide analysis of genes and proteins affected by Rad18 expression, as well as by the identification of Rad18 substrates in GCSCs. We will also generate a proof-of-concept for a role of Rad18 in sustaining glioblastoma proiliferation in preclinical models using both wild-type and Rad18 knock-out mice. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_db4c505020bebfa2fb6acba203da3e18 | Impact of a Typhoid Conjugate Vaccine Campaign on Antimicrobial Use in Harare, Zimbabwe | Wellcome Trust | Biomedical Research and Training Institute | HRCS22_16112 | Typhoid fever is a common cause of non-specific febrile illness in low-resource settings. Empirical treatment for typhoid may be a major driver of AMR in typhoid-endemic communities, where estimates suggest that up to 25 additional cases receive antimicrobial treatment for each one confirmed. Harare in Zimbabwe has experienced a major increase in typhoid since 2016, with recent emergence of ciprofloxacin-resistance. In February 2019 a mass typhoid vaccine campaign was performed, targeting infants and children living in 9 affected suburbs with the new typhoid conjugate vaccine (TCV). In work being performed at primary health clinics in these densely-populated suburbs as part of the FIEBRE study, which aims to assess the causes of febrile illness in low-resource settings, we have already identified a significant reduction in typhoid in vaccinated children. In this project our key goals are to investigate the impact of the 2019 mass TCV campaign on antimicrobial resistance in S. Typhi and on antimicrobial prescribing and related practices in community clinics. Defining these effects will have major policy implications for TCV use, both locally, in determining the benefits of further routine/repeat vaccination, and internationally to inform estimates of the direct and indirect impacts on AMR infection and antimicrobial use. | 3.4 Vaccines | 6project_grants_public
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gen_156df0077ff39bd9ec6e643d49f29902 | Defining NRF2-independent ROS management as bottleneck to tumor initiation | Worldwide Cancer Research | New York University | HRCS22_16120 | Cancer is generally viewed as a genetic disease, which develops when cells acquire mutations in proto-oncogenes and tumor suppressors. These mutations are thought to progressively derail tissue homeostasis, allowing for an expansion of tumorigenic clones with unlimited proliferative potential that fuels long-term tumor growth. Surprisingly, recent mutational analyses of physiologically normal skins unveiled a mutational spectrum and burden that is similar to what had been reported for squamous cell carcinomas (SCCs). Additionally, intravital imaging revealed that skin epithelial progenitor cells (EPCs) with oncogenic mutations persist only transiently and are primarily outcompeted by normal EPCs. These observations, along with stereotypic transcriptional and metabolic changes, which distinguish tumor propagating SCC cells (TPCs) from normal EPCs, suggest that epigenetic adaptation is critical for tumor initiation and persistent expansion. Still, the mechanisms facilitating this epigenetic and metabolic rewiring are largely unknown. Here, we will test the hypothesis that de novo Paired-like homeodomain transcription factor 1 (PITX1) expression facilitates the epigenetic and metabolic reprogramming of KrasG12Dmutant EPC into TPCs. PITX1 dependent changes in chromatin accessibility will enhance self-renewal and increase cell survival by reducing Ras generated reactive oxygen species (ROS). Specifically, we will (1.) determine how PITX1 cooperates with KrasG12Das they reprogram the transposase accessible open chromatin of homeostatic EPCs into the TPC specific epigenetic landscape; (2.) measure how these changes in chromatin accessibility influence ROS management; and (3.) determine if PITX1 dependent antioxidant production is a rate limiting step for tumor initiation. The results of our proposed research are expected to illuminate how oncogenic stress co-operates with sequence specific transcription factors to epigenetically rewire a homeostatic state into a tumorigenic epigenome, which allows TPCs to meet the metabolic demands required for tumor expansion. Once identified, these mechanisms could improve the early diagnosis and prevention of this exceedingly common and deadly human cancer. | 1.1 Normal biological development and functioning | 6project_grants_public
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gen_ec4962254d6cab4c2bef16eeb33d31fb | Preclinical development of antisense oligonucleotide therapy for RIPOR2-associated adultonset hearing loss | Royal National Institute for Deaf People | Radboud University Nijmegen Medical Centre | HRCS22_16125 | We recently identified a 12-nucleotide deletion in RIPOR2 (rs760676508) as a frequent cause of dominantly inherited adult-onset sensorineural hearing loss (DFNA21). Based on the allele frequencies in gnomAD, it is estimated that ~30,000 individuals in Northwest Europe are at risk to develop hearing loss due to this RIPOR2 variant. The mutated protein exhibits an aberrant localization in stereocilia. The proposed project builds on these findings and aims to put a genetic treatment on the horizon of DFNA21 patients. The age of onset and progressive nature of the hearing loss provide a window of opportunity for therapeutic intervention. This, together with the high prevalence, makes DFNA21 an important target for therapy development. As the 12-nucleotide deletion in RIPOR2 is indicated to have a dominant negative or toxic gain of function effect, we hypothesize that suppression of mutant RIPOR2 synthesis will prevent or delay the onset and/or progression of the hearing loss. To test this therapeutic strategy, the aims of the project are: 1)To design and test antisense oligonucleotides (AONs) for effective and specific targeting of the mutant RIPOR2 (pre-)mRNA for degradation in HEK293T and patient-derived cells. 2)To provide insight into the feasibility of AON-mediated therapy for DFNA21 in Δ12-nt Ripor2 mutant mice . Allele-specific quantitative PCR will be employed to demonstrate AON-effectivity and specificity in HEK293T cells transfected with plasmids encoding mutant and wildtype RIPOR2 and in patient-derived fibroblasts and otic progenitor cells. Audiometric testing and (immuno)histology will be the readouts for therapeutic efficacy in the DFNA21 mouse model. | 5.2 Cellular and gene therapies | 6project_grants_public
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gen_67a2749fc72a81a51cca8712f9289f03 | Characterising the role of RET in breast cancer brain metastasis as a facilitator of colonisation and a novel targeted therapy | Breast Cancer Now | Royal College of Surgeons in Ireland | HRCS22_16127 | Brain metastasis occurs in 10-30% of breast cancer patients and is fast becoming the foremost clinical challenge in the management of metastatic disease. Limited therapeutic options exist for patients with brain metastasis and the current treatment paradigm consists of surgical resection, stereotactic radiosurgery and whole-brain radiation. Clearly, there is an urgent need to better understand the mechanisms of breast cancer metastasis to the brain and to define novel therapeutic targets. Recent comprehensive sequencing studies from our group and collaborators have revealed a number of brain metastasis enriched oncogenic alterations with potential clinical significance. Aims: We aim to determine whether altered aberrant RET signalling in metastatic breast cancer is a key mediator of tumour colonisation of the brain. We also aim to determine the efficacy of RET inhibition to abolish cell growth and survival of breast cancer brain metastatic cells. Technique and Methodology: To address the suitability of RET as a target we will use both genetic and pharmacological inhibition of RET in comprehensive in vitro, ex vivo and in vivo pre-clinical models of breast cancer brain metastasis representing all three clinical subtypes. In vitro experiments will be accompanied by functional interrogation while in vivo experiments will be complemented by next-generation sequencing of the brain invading tumours. Impact on breast cancer research: The outcomes of this project have the potential to significantly enhance our understanding of the oncogenic significance of recurrent, acquired aberrations in the RET pathway in breast cancer brain metastasis. This project has the potential to uncover the clinical utility of brain metastasis-acquired clinically actionable alterations that could lay the foundations for a clinical trial utilising RET inhibition for patients with breast cancer brain metastasis. | 4.1 Discovery and preclinical testing of markers and technologies | 6project_grants_public
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gen_184fb2511af737ecc47b0160f942738d | Improved surveillance of zoonotic Mycobacteria through rapid direct detection and genotyping in livestock, wildlife, and their environment from low-resource areas in South Africa. | Wellcome Trust | Stellenbosch University | HRCS22_16129 | Recent studies in Africa and India (countries with high TB- and HIV-burdens) reported increased frequency of zoonotic tuberculosis (zTB) in humans caused by other members of the Mycobacterium tuberculosis complex (MTBC) like M. orygis, indicating that M. bovis infection may be an inadequate proxy for zTB. Similarly, nontuberculous mycobacteria (NTM) lung disease in people is more frequently reported in Africa because of environmental NTM like M. avium complex. NTM are naturally resistant to various drugs commonly used to treat MTBC infection and are often indistinguishable from MTBC when conventional MTBC “specific” immunological tests are used in humans and animals. Consequently, the management and treatment of infected patients are substantially different and complicated by the absence of appropriate culture-independent tests for the combined detection and differentiation of MTBC and NTM. We hypothesize that zoonotic pathogens like M. orygis and M. avium complex are more abundant in livestock, their environments and nearby wildlife than previously thought, especially in areas with immunocompromised people, leading to potentially high transmission risk interfaces. The goal is to develop culture-independent detection and genotyping tests to enhance zoonotic Mycobacteria spp. detection and differentiation directly from livestock specimens collected from low-resource areas, their environment and near-by wildlife reservoirs. | 2.2 Factors relating to physical environment | 6project_grants_public
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gen_689ecadafb4996278c5e4c8b07f6e97a | PPS - RTI | Duchenne UK | RTI International | HRCS22_16136 | This is a collaboration funded by Duchenne UK. It involves RTI International, Parent Project Muscular Dystrphy and Newcastle University, who are all recepients of funding based on their contribution. This collaborative project will assess and explore clinician, patient, and caregiver attitudes, priorities, and risk tolerance regarding gene transfer technologies. These technologies offer great promise to be disease modifying but come with risks and burden. The study will employ a research and community engagement approach previously developed by Holly Peay at RTI and the collaborating Parent Project Muscular Dystrophy (PPMD) team. Instruments from the prior PPMD gene therapy preference study will be revised to meet current state of the science and will be reused in the proposed study. Data will be collected in the United States and the United Kingdom. Data on attitudes, priorities, and risk tolerance will be compared across the countries. | 7.1 Individual care needs | 6project_grants_public
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gen_3806d039adf3dd495e3f5a04aff46c97 | Determining the neuroprotective and neurorestorative efficacy of AAV-hGDF5 in the AAV-α-synuclein rat model of Parkinson’s. | Cure Parkinson's | University College Cork | HRCS22_16139 | In Europe, 1.2 million people have Parkinson’s disease (PD), with a total socioeconomic cost of €13.9 billion per annum, which will double by 2030. No current therapy stops the symptoms of PD from worsening. This project proposes that a neurotrophic factor called growth differentiation factor 5 (GDF5) can be applied as a therapeutic to slow or prevent disease deterioration. GDF5 has known neurotrophic effects in preclinical models on midbrain dopaminergic neurons, the cells that degenerate in this disorder. To date, clinical trials of neurotrophic factors have used intracerebral delivery of either glial cell line-derived neurotrophic factor (GDNF) or neurturin (NRTN), but disappointingly, none of the trials have reached their primary end-point and thus are deemed to have failed. GDF5 is distinct from these two neurotrophic factors, in that it acts through a different signalling mechanism. Here the neuroprotective efficacy of an adeno-associated viral vector carrying the GDF5 transgene (AAV-GDF5) will be assessed in the rat α-synuclein model of PD. They will compare the effects of intrastriatal delivery of AAV-GDF5 with those of AAV-GDNF, in the AAV-a-synuclein rat model of PD. They will determine if this molecular therapy can protect dopamine neurons and their axons against a-synuclein-induced degeneration, to maintain brain dopamine levels and improve motor function. In parallel, they will study the protective effects of GDF5 treatment on cultured dopaminergic neurons which have a-synuclein mutations. Specifically, we will evaluate the effects of GDF5 on dopaminergic neuron survival, neurite growth and arborisation, in embryonic rat midbrain primary cultures and in induced pluripotent stem cell (iPSC)-derived dopaminergic neurons carrying SNCA triplication or the A53T mutation, both of which are common mutations in familial cases of PD. Overall, this research will lay the foundation for the translation of GDF5 viral vector therapy to clinic trials for PD. | 5.2 Cellular and gene therapies | 6project_grants_public
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gen_567c42aca34551493d87189788a1bf64 | Notch3 as a regulator of cancer-associated fibroblast reprogramming and functions in intestinal cancer | Worldwide Cancer Research | Alexander Fleming Biomedical Sciences Research Center | HRCS22_16166 | The Notch signaling pathway plays an important role in development, homeostasis, and disease, such as cancer, where its therapeutic potential is under consideration. However, the role of individual receptors, their cell-specific functions, and their implication in cancer therapy is not yet fully understood. Notch3 is of particular interest, as it is overexpressed in colorectal cancer (CRC) and associated with worst prognosis. Our preliminary data suggest that in patients and animal models of CRC, Notch3 is predominantly expressed in cancer-associated fibroblasts (CAFs) and more specifically in intratumoral perivascular fibroblasts. However, the mechanisms driving Notch3 activation in fibroblasts and its role as a regulator of CAF reprogramming and downstream functions are not known. In this proposal, we bring forward the hypothesis that endothelial-specific Notch ligands can activate Notch3 signaling in adjacent perivascular fibroblasts, leading to their activation and downstream functions associated with either or both angiogenesis and cancer cell proliferation, ultimately leading to tumor growth. Notch3 inhibition could thus have a therapeutic effect either alone or in combination with standard therapy. To address this hypothesis, we will combine in vitro and in vivo genetic targeting, 2D and 3D cell co-culture techniques, high-throughput single-cell, and bulk RNA sequencing, and mouse models of disease. We expect that this study could lead to a better understanding of the role of fibroblast-specific Notch3 in CRC and the potential of its inhibition in the clinic. In addition, it will provide further insight into the mechanisms driving CAF reprogramming and functions and thus help identify novel targets for therapeutic approaches, as well as diagnosis and patient stratification. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_cc1c24b75904911738d57444b0766583 | Pre-clinical evaluation of lonafarnib as a treatment for Parkinson's disease | Cure Parkinson's | Northwestern University | HRCS22_16195 | Genetic and pathological evidence strongly suggests that alpha-synuclein (a-syn) accumulation and lysosomal dysfunction are major contributors to Parkinson’s disease pathogenesis. Dr Mazzulli's group recently discovered a novel mechanism for a-syn-induced toxicity and lysosomal dysfunction using patient-derived iPSC-midbrain neurons. They found that a-syn accumulation impedes the trafficking of lysosomal hydrolases by disrupting a SNARE protein called ykt6. Ykt6 preferentially enhances the trafficking of lysosomal proteins, including beta-glucocerebrosidase (GCase) between the endoplasmic reticulum (ER) and the Golgi. However when a-syn accumulates, it aberrantly interacts with ykt6 and impedes its ability to traffic hydrolases. This results in lysosomal dysfunction, further perpetuating and augmenting a-syn accumulation. The team have discovered a novel way to rescue lysosomes by activating ykt6 through small molecule farnesyltransferase inhibitors (FTIs). Ykt6 is a unique SNARE in that it is inhibited by farnesylation, which keeps it in a locked, inactive conformation. Non-farnesylated ykt6 promotes an open, active conformation allowing it to bind to its cognate binding partners syntaxin 5 and bet1 at the cis-Golgi and promote trafficking. Blocking ykt6 farnesylation, either genetically or pharmacologically, was found to dramatically rescue lysosomal hydrolase trafficking and function including GCase activity. Using a previously established farnesyltransferase inhibitor (FTI) called LNK-754, 1-to-10 nanomolar concentrations could activate ykt6 and enhance lysosomal GCase by 2 fold in patient cultures and mouse brain, which was sufficient to reduce pathological a-syn. Dr Mazzulli's group's new, unpublished data shows that ykt6 is present in red blood cells, and that FTI treatment actives ykt6 in blood and brain to a similar extent. This provides a unique opportunity to track active ykt6 in RBCs as a marker of mechanistic target engagement for future clinical trials. While LNK-754 is a promising FTI, it requires extensive long-term safety assessment prior to treating PD patients. However, another FTI called Lonafarnib, has already passed long-term clinical safety tests and is FDA approved for the treatment of Progeria. To determine if FTIs hold promise as a disease altering PD therapy, we will determine if Lonafarnib can activate ykt6 and lysosomes in patient cultures and brains of a-syn transgenic mice. They will measure RBC ykt6 from lonafarnib-treated mice, to assess its potential as a biomarker for future clinical trials. At the end of the funding period, the project aims to determin if Lonafarnib can activate the ykt6-lysosomal pathway and reduce a-syn pathology in the brain, after oral administration. Since the mechanism for how FTIs enhance lysosomal function was uncovered here, they are uniquely positioned to assess the utility of RBC ykt6 as a blood biomarker to track mechanistic target engagement. If successful, they hope to translate these findings into PD patients as a novel disease modifying therapy within 2 years. | 2.1 Biological and endogenous factors | 6project_grants_public
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gen_65734e05463318635939a86c5d427b54 | Uncovering the effects of DNA replication stress on cell fate determination in cancer and stem cells. | Worldwide Cancer Research | University of Milan | HRCS22_16200 | Several studies have indicated that most cancer cells are associated with stress caused by the perturbation of DNA replication inducing replication stress (RS). RS and in general genome instability are major causes of genetic and epigenetic heterogeneity in human tumors. However, despite this heterogeneity, tumor mass and metastasis display stereotypical behaviors that allow them to invade surrounding tissues and escape immune surveillance. These features are remarkably similar to the ones displayed by trophoblast cells supporting placenta development. Using mouse embryonic stem cells (ESCs) we have recently found that RS-mediated activation of ATR and CHK1 promotes the expression of thousands of genes many of which involved in trophoblast differentiation, suggesting that RS can impact on cell fate determination in stem cells. The activation of several of these genes is coordinated by DUX, the master regulator of the two-cell stage in mouse ESCs, which we showed to be required for multinucleated trophoblast giant cells differentiation in response to RS. DUX and its human ortholog DUX4 are suppressed in normal adult cells. However, they are specifically reactivated in tumors where they promote the emergence of trophoblast-like features. Here we will study the molecular mechanisms linking RS to trophoblast activation in ESCs, identify pathways shared between placenta and cancer cells and uncover the mechanisms that suppress placenta activating mechanisms in adult somatic cells. Our studies will set the stage for targeting these pathways in order to develop new and effective therapeutic strategies to eradicate tumors. | 2.1 Biological and endogenous factors | 6project_grants_public
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