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gen_0be1c7ae5c3aa742530fb52e2d396b03 | Contribution of fatty acid metabolism to the advanced and metastatic phenotype of pancreatic cancer | Worldwide Cancer Research | Instituto de Investigación Sanitaria Aragón | HRCS22_13690 | Pancreatic Ductal Adenocarcinoma (PDAC) is an extremely lethal disease due to the current lack of effective therapies and extreme malignancy of the tumours once diagnosed. We have recently shown that PDAC is hierarchically organised with Cancer Stem Cells (CSCs) constituting a major source for disease progression, including metastasis and relapse following chemotherapy. Interestingly, increased lipid scavenging and aberrant fatty acid metabolism have been linked to pancreatic tumour progression and poor prognosis in PDAC patients. We have recently reported that, in contrast to differentiated tumour cells, pancreatic CSCs are highly dependent on mitochondrial oxidative phosphorylation (OXPHOS, Sancho et al, Cell Metabolism 2015). This metabolism confers the ability of using a wider range of substrates able to feed the TCA cycle, including fatty acids. Now, our preliminary results indicate that: 1) CSCs store and metabolise fatty acids for full tumorigenic capacity; 2) Energy deprivation promotes a highly dedifferentiated and aggressive phenotype through PPARdelta. We hypothesise that CSCs are able to modulate lipid storage/utilisation conferring them with high resilience and plasticity to adapt to the changing and challenging conditions during tumour progression and metastasis. Thus, in the present project we aim to analyse the specific role of fatty acid metabolism in the advanced and metastatic phenotype of PDAC by addressing the following three aims: 1. To study the role of lipid uptake and storage in CSCs to cope with situations of metabolic stress. 2. To investigate the role of PPARd in the acquisition of an advanced/metastatic phenotype in pancreatic cancer 3. To validate new therapeutic strategies targeting lipid metabolism Our ultimate aim is to identify and validate most effective CSC-targeting strategies with great translational potential, to improve the still miserable prognosis of PDAC patients. | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_635bd8cd7972480f4c0ea93ac63abafb | Tools to Highlight Impact and Aid Curation of Scholarly Outputs | Wellcome Trust | American Society for Cell Biology | HRCS22_13707 | The proliferation of scholarly content and implementation of transparent peer review are creating challenges for readers and evaluators to assess research significance and review outcomes, and for journals to curate field-specific content. We propose controlled experiments in which we test the utility of badges and impact statements to signal the significance of articles published by the American Society for Cell Biology (ASCB) in its research journal, Molecular Biology of the Cell (MBoC). We will devise badges that alert readers to article attributes such as new concept, broadly relevant, technical advance, teaching resource, etc. We will also experiment with new peer review processes, including a streamlined process designed to concisely identify points of significance and key issues, and one in which authors, reviewers, and editors work together to craft concise impact statements for display on articles. The effects of these innovations will be assessed relative to traditional practices by comparing article-level metrics including article views, downloads, and Altmetrics attention scores and by surveys. We will then use these innovations and the expertise of ASCB members, including early career scientists, to curate preprints and articles in other venues with the goal of providing standard, portable tools for use by other publishers. | No Research Activity assigned | 6project_grants_public |
gen_2fd8b1bedcd8851386a3bf43a9a4b34a | Filling in the gaps during a crisis of care: social and political constructions of lay care work during the HIV/AIDs epidemic and the Covid-19 pandemic in South Africa. | Wellcome Trust | University of the Western Cape | HRCS22_13713 | The project aims to explore the various social and political constructions of lay care work during the Covid-19 pandemic and the early stages of the HIV/AIDs epidemic in Cape Town. It will analyse the tensions and possibilities that arise when informal, self-organised and localised care work done by ordinary people interacts with the formal health system, considering how this represents a potential for social change in the health system and broader society. Analysis will draw on Feminist care theory and De Certeau's concept of "tactics" and "strategies", situating the project in a broader critique of the ways in which the dominant neoliberal and capitalist order produces a "crisis of care" that marginalises care work and stifles possibility for meaningful collaborations between the formal health system and ordinary people doing this work. Research will involve archival and document-based data such as meeting recordings, media pieces, policy documents, academic and NGO reports, and documentary films regarding lay care work and community-based care during Covid-19 and the early stages of the HIV/AIDS epidemic (90s-early 2000s). It will also draw on in-depth interviews with participants who were actively involved in and/or able to reflect on the provision of place-based, lay care during both cases. | No Research Activity assigned | 6project_grants_public |
gen_ee8f01dd9c1ef3bd9097c8ce4b50a15d | PRECISION - supplementary award | Cancer Research UK | University of Texas MD Anderson Cancer Center | HRCS22_13775 | Background Ductal carcinoma in situ (DCIS) now represents 20-25% of all breast neoplasia. This is due to large-scale detection by widely adopted population-based breast cancer screening programs . As a result, thousands of women are confronted with DCIS each year: more than 8,000 in the UK, 2,300 in the Netherlands, and over 50,000 in the US. Conventional management includes surgery, supplemented by radiotherapy and/or endocrine therapy, but overtreats the majority of DCIS as ~1% recur annually and breast cancer mortality is ~3% at 20 years. Uncertainty as to which DCIS lesions will progress to invasive cancer or, after excision, which will return with recurrent DCIS or invasive breast cancer drives this overtreatment. Distinguishing DCIS that may progress to lethal disease from the majority of harmless DCIS is therefore an urgent need to save thousands of women with low risk DCIS the burden of radical treatment without any survival benefit. Aim We aim to reduce the burden of overtreatment of DCIS (surgery, radiation therapy, hormonal therapies) through the development of novel tests that promote informed and shared decision-making between patients and clinicians, without compromising the excellent outcomes for DCIS management presently achieved. Methods First, three large retrospective DCIS cohorts (and supplementary sources) will be collected enabling subsequent in depth molecular studies. Second, extensive genomic characterisation, immune profiling and imaging analysis will be performed. In vivo and in vitro modelling will be performed to study the biology of DCIS in detail. Finally, all clinical, immune, and molecular data will be incorporated into a clinical risk prediction model. This risk prediction model can be validated in three prospective DCIS trials. Specifically, in the current project we will a.) collect tissue and blood samples from these trials and b.) start validation of the biomarkers detected in the retrospective series. How the results of this research will be used The discoveries from our laboratory studies, including a risk stratification model, will be cross-validated in prospective trials of DCIS active surveillance versus conventional treatment (the LORIS, LORD and COMET trials). As such, the main result of this study will be that we can identify a group of women for which active surveillance for DCIS could be a safer alternative to intensive treatment. Ultimately, this may also contribute to a more reassuring perception of risk regarding non-life threatening precancerous lesions in general, reducing anxiety and preserving quality of life. | 2.6 Resources and infrastructure (aetiology) | 6project_grants_public |
gen_cee277dd4d3fff26bd3c01a14f1b1071 | Social security for children with disabilities in rural South African communities: family caregiver, health worker, civil society, and policy implementer perspectives on access to and the use of the Care Dependency Grant in the Cape Winelands | Wellcome Trust | Stellenbosch University | HRCS22_13786 | In South Africa, state-funded social protection for disabled children has primarily been through the Care Dependency Grant (CDG). The CDG is distributed to the caregivers of these children and provides important financial assistance, but it is under-researched. Little is known about caregivers’ access and utilisation of the CDG, what the value of complementary interventions might be, how doctors assess need and deservingness, and how government agencies conceive of and communicate about the CDG. The proposed study will investigate these and other questions in a qualitative study using ethnographic and participatory methods, with a specific focus on the Cape Winelands district. Participants will include caregivers of children with disabilities, assessing doctors, South African Social Services Agency (SASSA) staff members, and organisations working with disabled children. Findings will be discussed with reference to broader debates around social protection, development, poverty alleviation, and access to health and education for disabled children. A better understanding of how this grant is conceived of, used, and distributed from the perspective of different stakeholders will build knowledge in this underdeveloped area. It will also produce important initial evidence for potential future interventions to improve the social protection of disabled children and their caregivers in South Africa. | 8.1 Organisation and delivery of services | 6project_grants_public |
gen_f550a07b390fe0c9a67f2758d61bf665 | Improving the prediction of endometrial cancer risk using genetics | Worldwide Cancer Research | QIMR Berghofer Medical Research Institute | HRCS22_13825 | Endometrial cancer (cancer of the uterine lining) is the most commonly diagnosed gynaecological cancer in developed countries, including Australia. Its incidence is rapidly increasing due to the ageing population and rising rates of obesity, the strongest known risk factor for endometrial cancer. This is a global problem, with a recent study reporting increased incidence rates of endometrial cancer in 26 of 43 countries studied. Unlike many cancer types, endometrial cancer-specific mortality has increased approximately 2% each year since 2008, in part due to its increased incidence. Whilst the link between obesity and endometrial cancer risk is well-recognised, the mechanism for how this occurs is unknown. Understanding which characteristics of obesity are responsible for this relationship would provide vital information not only for informing endometrial cancer risk but also understanding the biology of this disease. How to use the information from obesity and other risk factors effectively to identify women at very high risk of endometrial cancer is not available. Harnessing these data would provide avenues for personalised risk prediction and targeted prevention interventions, including bariatric surgery. Our research team leads the world’s largest genetic study of endometrial cancer through co-ordination of the Endometrial Cancer Association Consortium and identifying several genetic variants associated with endometrial cancer risk by genome-wide association study. We will use these genetic data to explore the relationship between endometrial cancer and specific obesity-related traits. We will construct endometrial cancer genetic risk scores, integrating genetic data from endometrial cancer risk factors to improve predictive capacity. Finally, we will assess the effect of intervention strategies on reducing endometrial cancer risk, providing essential data for clinical implementation of genetic risk scores for endometrial cancer prevention. | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_b7217427976bbf234e2b66a35b98bc13 | Assessment of the impact of mycotoxins on the epigenome and their synergistic role with EBV in endemic Burkitt lymphoma in African children | Children with Cancer UK | International Agency for Research on Cancer | HRCS22_13849 | Chronic exposure to toxins (Mycotoxins) produced by moulds (Fungi) and infection with oncogenic viruses have been shown to increase a person’s chances of developing cancer; for example, the synergy between Aflatoxin B1(AFB1) and Hepatitis B virus infection have been shown to increase the development of Liver cancer 1. Burkitt’s lymphoma (BL) is a childhood cancer of the lymphatic system that is known to occur when the B-lymphocyte is infected with Epstein Barr virus 2, endemic Burkitt’s Lymphoma variant (eBL) occurs mostly in African regions prone to EBV and malaria infections 3. In addition, persons living in African regions are faced with unavoidable mycotoxins exposure. Mycotoxins are problematic in terms of acute exposure in staple crops especially in low- and middle-income countries (LMICs), leading to mycotoxicosis outbreaks (e.g. aflatoxicosis) 4. A recent study estimated that about 60 to 80% of world’s food crops are contaminated with mycotoxins, meaning that dietary mycotoxins’ exposure is unavoidable 5, 6, 7. Generally, mycotoxins have caused both economic 8, 9, 10, 11 and health problems 12 such as carcinogenicity, hepatotoxicity, and genotoxicity. Therefore, chronic exposure to mycotoxins coincides with higher incidence of eBL across regions of Africa. Previous studies within our branch demonstrated that exposure to certain mycotoxins promotes EBV infection, and children in regions of Africa with high mycotoxin exposure and high incidence of BL also have higher EBV infection levels | 2.2 Factors relating to physical environment | 6project_grants_public |
gen_fb0bf5f01ec0788f101a2c66dc7a95a8 | Liraglutide: A phase II, randomized, double-blinded, placebo-controlled trial of Liraglutide in Parkinson’s disease (Extension 1) | Cure Parkinson's | Cedars-Sinai Medical Center | HRCS22_13854 | Extension to MT011. See above. | 6.1 Pharmaceuticals | 6project_grants_public |
gen_cd0d1462819e5d8ae760e511ee9978c2 | Silence, solitude, and serotonin: how hearing loss and social isolation converge to influence serotonergic regulation of the auditory midbrain | Royal National Institute for Deaf People | Indiana University | HRCS22_13910 | The social isolation that often accompanies hearing impairment in older adults co-occurs with other health concerns, including depression, anxiety, and cognitive decline. A contributing factor to these negative outcomes may be dysfunctional communication driven by deficits in auditory processing and perception. We will assess whether noise-induced hearing loss and social isolation additively influence regulation of the auditory system by serotonin. To test this hypothesis, we will noise-expose CBA/CaJ mice in young adulthood, resulting in exaggerated age-related increases in auditory thresholds. Noise exposure or sham treatment will be factorially combined with a one-month period of individual or social housing in postbreeding mice, to create four treatment groups. Three different outcome measures will be assessed: 1)_x0001_The density of axons labelled with an antibody to the serotonin transporter will assess plasticity in serotonergic projections to the inferior colliculus (IC). 2)_x0001_The numbers of neurons in the dorsal raphe nucleus (DRN) that double-label for antibodies to tryptophan hydroxylase and the immediate early gene product cFos will assess the functional activation of serotonergic neurons during a social encounter. Analysis will focus on DRN subregions that project to the IC. 3)_x0001_Anxiety-like behaviors in the elevated plus, open field, and social encounter tests will be used to assess the engagement of broad mechanisms regulating affective behavior. The predicted additive effects of hearing loss and isolation on serotonergic axons in the IC, and isolation-only effects on the activity of DRN neurons, could create dysfunctional regulation of auditory processing during social encounters. | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_63a21e7a089e8aa4079861a955044896 | The development of a best-in-class iron chelator to prevent oxidative stress, iron regulated cell death (ferroptosis) and synucleinopathy as a treatment for Parkinson’s Disease, to-gether with the integration of biomarkers of target engagement and efficacy. | Cure Parkinson's | Centre Hospitalier Universitaire de Lille | HRCS22_13946 | Excessive labile iron in the Substantia Nigra pars compacta (SNpc) is a pathognomonic hallmark of PD and leads to increased production of noxious reactive oxygen species. Alpha-synuclein regulates dopamine and iron transport, with PD associated mutations in this protein causing functional disruption of these processes. It has recently been discovered that these alterations can trigger susceptibility to an iron-dependent cell death pathway with unique lipid peroxidation signatures called ferroptosis. Interestingly, iron accumulation and ferroptosis are highly sensitive to iron chelation. As demonstrated with the prototype chelator deferiprone, iron can be scavenged from labile iron complexes in the brain and transferred (conservatively) either to higher-affinity acceptors in cells or extracellular transferrin. Promising preclinical and clinical proof of concept trials have led to several current large randomized clinical trials (FAIR PARK II) that aim to demonstrate the concept of conservative iron chelation. A new iron chelator, SP-420 (invented by Prof. Ray Bergeron, University of Florida, and in clinical development by AbFero Pharmaceuticals) has significant advantages over deferiprone, including superior potency, tolerability, and safety (lack of neutropenia/agranulocytosis). A European consortium has been set up to launch the preclinical validation of SP420 in PD models and is funded by the European Commission (Eurostars program). The Eurostars work package will allow definition of 1) the pharmacokinetics (Pronexus AB, Dr. Kehr, Sweden), the in vitro molecular mechanisms (CHUL, Prof. Devos, France) 3) the in vivo validation in the subchronic MPTP mouse, 6-OH dopamine rats and in the preformed fibrils of the alpha synuclein mouse model (Erasmus University, Prof. Mastrobaradino, The Netherlands). Despite the quality of the Eurostars initiative, additional challenges to the success of a P2 trial remain. Indeed, while the concept of effective neuroprotection in PD has continued to excite interest, there has been more than 40 years of failure in neuroprotection. A key solution to overcome this major challenge is to better characterize the best population and the best doses, thus enhancing the chances of a successful clinical trial. Thus, the goal of this project is to validate neuroprotection induced by SP-420 in two additional pivotal in vivo PD models (i.e. the subchronic MPTP-treated aging mouse and the Thy1-a-syn mouse model, not funded by the Eurostars program) and associated with target engagement and the theragnostic biomarkers (not studied in the Eurostars program). Several new dry and wet biomarkers will be additionally be assessed including: MRI sequence of magnetization transfer associated with the T2* sequence (i.e. iron in and outside neuromelanin), PET scan [64Cu]-ATSM (i.e. lipid peroxidation preceding cell death) associated with GFAP (i.e. astrocytosis) associated with light chain neurofilament (i.e. axonal destruction), selenium (i.e. selenoprotein GPX4 = major antioxidant enzyme for lipid) associated with 4-HNE, MiRNA involved in ferroptosis associated with ferritin and alpha synuclein. The results will further validate the potential of SP-420 as a viable PII PD candidate, allowing AbFero to facilitate regulatory interactions necessary to support clinical trials in patients with PD, and increasing confidence in the investor and clinical community who will be key partners for AbFero as the substantial financial commitments are sought for PII and PIII studies. | 5.1 Pharmaceuticals | 6project_grants_public |
gen_7a22b8bf23c4f9bddc1d26b78136023e | Enteric Pathogens and Post-discharge Outcomes among Children in sub-Saharan Africa and South Asia (The EPPO-SASA Study) | Wellcome Trust | KEMRI Wellcome Trust Research Programme | HRCS22_13957 | Enteric pathogens are a major cause of hospitalisation among children and are associated with diarrhoea, enteric dysfunction, dysbiosis, and increased risk of mortality and readmission especially in low- and middle-income countries. When admitted to hospital, treatment failure may occur despite following guidelines. Furthermore, carriage of pathogens or disturbance in the intestinal microbiome may be hospital-acquired and/or resistant to first-line antimicrobials potentially increasing the risk of readmission. I aim to determine whether molecular evidence of enteric pathogens and gut dysbiosis at hospital discharge, when children were judged as clinically well, is associated with readmission post-discharge among children across the nutritional stratum. This case-control study is nested within the completed CHAIN cohort study (six countries) that aims to characterise demographic, clinical, and social risk factors for mortality among children <2 years old, with an extensive nested case-cohort systems biology sub-study targeting mortality. Cases will be children readmitted to hospital within 6 months of index discharge and controls will be age, nutritional stratum and site matched children who were not readmitted. I will utilise targeted faecal TaqMan multiplex PCR (Kilifi, Kenya), culturomics and metagenomics (Sanger Institute, UK). Findings may support policies for post-discharge screening, prophylaxis, targeted diagnostics, and revision of treatment protocols. | 2.2 Factors relating to physical environment | 6project_grants_public |
gen_57027a0cb8aef15033ac39477a2a5a07 | RECOVER (Real World Clinical Outcomes with Novel Modulator Therapy Combinations in People with CF) | Cystic Fibrosis Trust | Children's Health Ireland at Crumlin | HRCS22_13961 | Triple combination CFTR modulator therapy (TCMT), has shown promising results on important health outcomes in clinical trials in PWCF and has been approved in the US for use in people>12 years of age with one or more copy of F508del. Approval in Europe is pending, subsequent to which the drug will be provided for use in PWCF in Ireland as part of a pre-existing agreement with the manufacturer. Clinical trials are highly monitored and tightly controlled, and regulators understand the importance of 'real world' data to ensure they help patients as they are supposed to and are safe when widely used. We have designed a real-world study involving children and adults with CF across eight paediatric and adult CF centres in the UK and Ireland in collaboration with CF registry of Ireland and the UK CF registry. We will be examining a wide range of well-established tests in these people, as well as some newer, more sensitive tests looking at how this new treatment might affect health and quality of life in PWCF. We will be looking at how PWCF feel about this new treatment, how it affects their quality of life and whether it affects their need for, or ability to take, other CF treatments. One of the key strengths of RECOVER will be the direct comparison of a 'control' group in UK centres (who do not yet have access to treatment) with an on-treatment group in Ireland. With a point of care 'registry style' database and data management by CFRI we will be in a position to produce real time data on the effectiveness of TCMT in the real world and hopefully, convince reimbursement agencies of the benefits of therapy. | No Research Activity assigned | 6project_grants_public |
gen_cfca34f1f6fde4ffb411423bce3e59d1 | Developing native strains of insect-killing Metarhizium spp. fungi to prevent malaria transmission in Burkina Faso | Wellcome Trust | Institut de Recherche en Sciences de la Santé | HRCS22_13969 | Despite efforts developing entomopathogenic fungi as biocontrol agents against disease vectors, expectations have not been met due to their relatively poor efficacy compared to cheaper chemical insecticides. The vast majority of mosquito control studies have focused on a single fungal isolate. However, the recent discovery that native strains of entomopathogenic fungi in Burkina Faso confer exceptionally high virulence against Anopheles gambiae provide new evidence that could transform the effectiveness of these biocontrol tools. These strains showed LT80 as low as 7 days, which is an unprecedented improvement over previous studies where LT80 values are ~10 days. The proposed research will investigate new ways to exploit local fungi strains for sustainable vectors control solutions. Specifically, using a combination of laboratory assays, semi-field experiments, and hut trials, I will investigate the practical utility of the native strain of Metarhizium from Burkina Faso for malaria vector control. This project will tackle the current challenges in the implementation of biocontrol strategies and will overcome the ecological barriers that have prevented the use of fungi for mosquito control and develop an effective entomopathogenic approach, which will be 1) applicable to other settings, 2) low-cost and biological, and 3) complementary to current vector control interventions. | 3.2 Interventions to alter physical and biological environmental risks | 6project_grants_public |
gen_567f6468ad03f1e0e112c724db15378a | A digital dashboard to support institutions implementing open science: Establishing a core set of open science metrics to track | Wellcome Trust | University of Ottawa | HRCS22_13974 | The completion of the proposed research program will result in two key outputs: 1) a core outcome set of open science (OS) metrics relevant to, and developed by, the biomedical community; and 2) a usable flexible, tailorable, and automated tool, developed using user-centred design best practices, that reports on these core OS metrics. Establishing a core outcome set of OS metrics is a vital step to move forward discussion around how to measure research(er) quality. Without consensus on what to measure, or how to measure it, even well intended institutions can’t easily consider incorporating metrics beyond those traditionally used (i.e., journal impact factor or number of publications). A core outcome set does not limit organizations from tailoring the collection of OS metrics, but ensures a standard set across organisations to enable national and international standardisation and comparison. By engaging with the research community at the onset of this program and throughout via an integrated knowledge translation approach, we can ensure that the tool we develop to report on the established core OS metrics meets the needs of the community and considers their concerns. Doing so ensures greater uptake. Further, through embedding considerations of equity, diversity, and inclusion in our design of the OS dashboard, we intend to create a tool that is globally relevant in biomedicine. This will ensure that our impact is as broad as possible and serves the entire biomedical community. By meeting our proposed aims, we will have achieved a ready to implement publicly available OS dashboard. | No Research Activity assigned | 6project_grants_public |
gen_cb46733854f3ce314377df6c2c11a4c3 | Accelerating Drug Discovery with Symbolic-Numerics in SciML | Wellcome Trust | Boston University | HRCS22_14003 | Pharmaceutical companies understand the need for modeling stochasticity, by which we can improve the reliability and effectiveness of drugs across the whole population. Our 2020 review in Trends in Pharmacological Sciences, one of the highest impact journals in pharmacology, argued that deterministic models that ignore stochasticity bias clinical and pre-clinical trial analyses. The quantitative systems pharmacology (QSP) groups within drug companies are the core units that model and predict patient outcomes, dramatically reducing the research and development timeline by predicting which drugs will fail before clinical trials begin. These groups have recently adopted stochastic dynamical models in order to better achieve their goals. Discussing with CJ Musante, Global Head of Pharmacology at Pfizer, the main reason that stochastic models are not more widely used is due to a lack of software that addresses the needs of QSP modelers. Stochastic models are more predictive of patient outcomes, but computationally expensive. Moreover, turnaround times needed by QSP teams are too short to make use of stochastic models with current software. This proposal addresses this problem, proposing to build software tooling which automates the construction and solution of stochastic models in a way that is orders of magnitude faster than what exists today. | No Research Activity assigned | 6project_grants_public |
gen_d6179e7774b38ede89a677d01cdb127a | Data-driven drug discovery for A-T – interrogation of dysfunctional pathways at single-cell resolution in cerebellar organoids | Action for A-T | QIMR Berghofer Medical Research Institute | HRCS22_14090 | Using a data-driven approach, informed by single-cell sequencing of a large cohort of ATM_x0002_deficient cerebellar brain organoids - the hypothsis is that computational prediction of drugs will allow selective, positive modulation of aberrant pathways and behaviour in the team's in vitro model of the A-T cerebellum. Further, the team will democratize this research space by sharing their data, placing the building blocks for expansion of this project to grow globally. | 1.1 Normal biological development and functioning | 6project_grants_public |
gen_a4d8dad4026b2da9b5bc8fe060a0d402 | Innovative methods for gene therapy in A-T | Action for A-T | University of Granada | HRCS22_14091 | This project will be looking at Innovative methods for the potential of delivering gene therapy in A-T | 5.2 Cellular and gene therapies | 6project_grants_public |
gen_0a6ad8a2d5b65b37a12332585eff8573 | Discovering new aminoglycosides to alleviate inner ear toxicity | Royal National Institute for Deaf People | Stanford University | HRCS22_14099 | Aminoglycosides are a class of widely used, broad spectrum antibiotics that cause hearing impairments in upwards of 20% of treated patients and even higher percentages if repeated treatments are needed or susceptible genetic mutations are present. Although aminoglycoside ototoxicity is a well-documented side-effect, there is still no FDA-approved treatment to prevent it. Despite the availability of newer, less ototoxic and nephrotoxic antibiotics, aminoglycosides are still among the most commonly prescribed class of antibiotics worldwide because of their efficacy, low costs, and low rates of antibiotic resistance. Indeed, aminoglycosides are designated as one of the critically important antimicrobials for human medicine. In the US, it is the first line of treatment for neonatal and peripartum sepsis and complicated urinary tract infection. In cystic fibrosis patients who are prone to recurrent sinopulmonary infection as most patients now survive into adulthood, repeated treatment with aminoglycosides is common with resulting hearing loss at rates up to 47%. There is clearly a pressing need to reduce aminoglycoside ototoxicity. Aminoglycosides cause permanent hearing loss resulting from the irreversible loss of cochlear hair cells. We have made significant progress in designing aminoglycosides with differential effects on the prokaryotic and eukaryotic ribosome to reduce ototoxicity while preserving antimicrobial activity in vitro and in vivo, devised novel chemical synthetic pathways, identified target sites on the aminoglycoside backbones to modify, and generated several lead compounds. The current proposal aims to: 1)_x0001_test and optimize lead compounds in in vivo ototoxicity and infection models 2)_x0001_test additional novel aminoglycoside analogues in vitro for ototoxicity and antimicrobial activities and ability to permeate hair cells. | 5.1 Pharmaceuticals | 6project_grants_public |
gen_5e6a6863485bf426599a7c8bfd7e5f86 | Preclinical development of an amelioration therapy for Dentatorubro-Pallidoluysian Atrophy | Ataxia UK | Inserm | HRCS22_14108 | Dentatorubro-Pallidoluysian Atrophy (DRPLA) is a polyglutamine ataxia caused by mutations in the ATROPHIN-1 gene, for which no cure is available. This group have significant experience in models of ataxia and spastic paraplegia with ataxia, and in particular of DRPLA. Following the recent success of antisense oligonucleotide (ASO) approaches in Huntington’s Disease - a polyglutamine syndrome with many genetic similarities to DRPLA - this group plan to apply their expertise to this preclinical study aimed at developing an ASO therapy for DRPLA. This group will test a batch of ASOs designed against the Atrophin-1 mRNA. The efficacy of the two best performing ASOs will be further studied in a well characterised mouse model (ATN1-65Q-FL). They plan to measure changes in the behavioural, histopathological and transcriptomic hallmarks of DRPLA. The group hope that at the end of this project, it may be possible to translate this therapy into a clinical trial for DRPLA patients. | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_16ece7846d935d935e76ee5cb7e6b113 | Graphene-based disruptive technologies | European Commission | CENTRO DE INVESTIGACION COOPERATIVADE ENERGIAS ALTERNATIVAS FUNDACION; HORIBA JOBIN YVON S.A.S.; Queen Mary University of London; Sorbonne University; BRETON SPA; University of Augsburg; BRUNO BALDASSARI & FRATELLI SPA | CORDIS-696656 | This project is the second in the series of EC-financed parts of the Graphene Flagship. The Graphene Flagship is a 10 year research and innovation endeavour with a total project cost of 1,000,000,000 euros, funded jointly by the European Commission and member states and associated countries. The first part of the Flagship was a 30-month Collaborative Project, Coordination and Support Action (CP-CSA) under the 7th framework program (2013-2016), while this and the following parts are implemented as Core Projects under the Horizon 2020 framework. The mission of the Graphene Flagship is to take graphene and related layered materials from a state of raw potential to a point where they can revolutionise multiple industries. This will bring a new dimension to future technology – a faster, thinner, stronger, flexible, and broadband revolution. Our program will put Europe firmly at the heart of the process, with a manifold return on the EU investment, both in terms of technological innovation and economic growth. To realise this vision, we have brought together a larger European consortium with about 150 partners in 23 countries. The partners represent academia, research institutes and industries, which work closely together in 15 technical work packages and five supporting work packages covering the entire value chain from materials to components and systems. As time progresses, the centre of gravity of the Flagship moves towards applications, which is reflected in the increasing importance of the higher - system - levels of the value chain. In this first core project the main focus is on components and initial system level tasks. The first core project is divided into 4 divisions, which in turn comprise 3 to 5 work packages on related topics. A fifth, external division acts as a link to the parts of the Flagship that are funded by the member states and associated countries, or by other funding sources. This creates a collaborative framework for the entire Flagship. | H2020-EU.1.2. / 1.2 Future and Emerging Technologies (FET) | 6project_grants_public |
gen_e2c9ce9a8c9b6ecfb8ff9188983bb500 | Intimate partner violence against women in low- and middle-income countries: associations with parenting practices and early childhood development. | Wellcome Trust | Associação Brasileira de Saúde Coletiva | HRCS22_14182 | The 2030 Agenda for Sustainable Development highlights the need to prevent and respond to violence against women and girls. It also affirms the need to invest in early childhood care for the promotion of sustainable development in low and middle-income (LMICs). Intimate partner violence (IPV) is one of the most common and extreme manifestations of gender inequality worldwide, and has a higher prevalence and more severe consequences for women and children living in LMICs. I aim to examine the association of IPV with parenting practices and early childhood development in LMICs. This will be done using data from nationally representative household surveys (DHS) carried out since 2010 in at least 10 LMICs, and a large population-based prospective cohort study in Brazil, following over 4,000 children born in 2015. A key objective of the project is to explore whether women´s mental health mediates the proposed associations, and the role of women’s empowerment levels in the associations under study. The empirical evidence generated from this project will contribute to increasing visibility of the intergenerational consequences of IPV on children and provide guidance for the direction of global resources to prevent gender-based violence. | 2.3 Psychological, social and economic factors | 6project_grants_public |
gen_17dfd315c8331f2682f3cea00fe55c68 | Identifying innate and adaptive immune mechanisms associated with fibrosis in animal models of RDEB | DEBRA | New York Medical College | HRCS22_14225 | We recently demonstrated that TGFβ signaling is activated in RDEB (col7a1-/-) mice as early as a week after birth in the interdigital folds of murine paw skin. At the same time, many critical genes involved in wound healing and fibrosis are significantly upregulated. In preliminary studies, we also observed infiltration of significant levels of neutrophils, macrophages, T cells and mast cells in the dermis of newborn and a week-old RDEB mouse skin. This inflammatory response is likely initiated by damage-associated molecular patterns (DAMPs), also known as sterile inflammation, as there is no apparent microbial-associated infection. Sterile inflammation has often shown to result in chronic inflammation and fibrosis. Surprisingly, all these immune cells are later (in two weeks) clustered around hair follicles. Such tropism of T cells to hair follicles resembles the features of skin resident memory T (TRM) cells, which provide rapid immune protection, however, when dysregulated, result in unwanted inflammation and fibrosis. Investigating the early events of sterile inflammation with subsequent microbialassociated infection is critical to understand the mechanisms of chronic inflammation and fibrosis in patients with RDEB. These results will facilitate the development of effective therapeutic strategies to prevent chronic fibrosis in patients with RDEB. | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_2a72ff736c62a437f0eb41c40b425fe1 | NT3 treatment for brain coding restoration after cochlear synaptopathy | Royal National Institute for Deaf People | University of Michigan Health System | HRCS22_14228 | After noise-exposure that produces TTS, and thus clinically ‘normal’ audiograms, there is nonetheless permanent damage to auditory nerve (AN) - hair-cell synapses. 'Hidden' hearing loss is a potential major health issue, as temporal bone and ABR studies suggest it is common in humans, causing difficulties understanding speech in noise. These deficits reflect temporal-coding problems likely due to loss of high-threshold, low-spontaneous rate ANFs, which are preferentially affected after TTS. The primary central targets of high-threshold ANFs reside in the small cell cap (SCC) of the cochlear nucleus (CN), which is prominent in humans. SCC neurons display large dynamic ranges and superior suprathreshold tuning and temporal coding, which are essential for speech perception in noisy environments. The SCC is a recipient and projection area of medial olivocochlear (MOC) neurons which minimize threshold shifts after noise damage, and thus likely also play a role in SCC circuits in hidden hearing loss. The overall hypothesis of this proposal is that the SCC plays a major role in suprathreshold sound coding and that this coding is highly susceptible to degradation by hidden hearing loss. We will elucidate the cochlea-SCC-MOC circuit in normal and noise-damaged animals with hidden hearing loss, using optogenetics, physiology and tract tracing. Furthermore, we will determine whether NT3 restoration of ANFs affects auditory processing in the SCC after noise damage. Cochlear delivery of neurotrophins in humans is easily achieved via trans-tympanic injections, suggesting a possible clinical intervention. | 2.1 Biological and endogenous factors | 6project_grants_public |
gen_cbf4e4602db01f5942203dae6a9108c4 | Accelerating the development of lorlatinib to improve cure rates for patients newly diagNOsed ALK-driven high-risk neuroblastoma | Solving Kids' Cancer | Children's Hospital of Philadelphia | HRCS22_14317 | Neuroblastoma, the most common solid tumor malignancy of childhood, encapsulates the full spectrum of cancerheterogeneity. This cancer of the developing peripheral sympathetic nervous system shows widely divergent clinical manifestations, with approximately half of patients exhibiting explosively malignant disease with high risk for fatality. Genetic interrogation of neuroblastoma has demonstrated that this observed clinical heterogeneity is molecularly driven. However, current therapy consists of a largely empiric selection of cytotoxic therapies followed by targeted immuNOtherapy used to prevent relapse once remission is achieved. Despite this intensive therapy, cure rates for patients with high-risk neuroblastoma have been stalled in the 50% range and those surviving often suffer lifelong toxicities including deafness, growth and skeletal deficiencies, hormonal dysregulation, learning disabilities and second malignant cancers. The disproportionately high mortality rate for patients with high-risk disease mandates a need for the development of molecular targeted therapies that will ultimately improve survival while minimizing the risk of late effects. Activating mutations in the ALK oncogene are the cause of the hereditary form of neuroblastoma, and importantly these mutations are present in 14% of patients newly diagNOsed with high-risk neuroblastoma, representing a tractable therapeutic target. In addition, emerging data have demonstrated that many newly diagNOsed patients have a hidden small percentage of ALKmutated neuroblastoma cells that ultimately lead to disease relapse, explaining the observation that ALKmutations are more common at relapse compared to diagNOsis. These finding led to our initial study of crizotinib, a first-generation inhibitor of ALK, as a potential treatment for neuroblastoma, and led to the current investigation of crizotinib in patients with newly diagNOsed high-risk neuroblastoma within the Children’s Oncology Group(COG). More recently, through a partnership with Pfizer Pharmaceuticals, we have discovered a highly specific and potent ALK inhibitor, lorlatinib, that has improved anti-neuroblastoma activity and provides a unique opportunity to achieve significant impact in neuroblastoma patients. The successful completion of this project will result in the dramatic transatlantic acceleration of lorlatinib use in parallel Phase 3 trials within COG and International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) that seek tosubstantially improve the event-free survival for patients with newly diagNOsed high-risk neuroblastoma whose tumors harbor an activated ALK gene mutation. | 5.1 Pharmaceuticals | 6project_grants_public |
gen_3d3fc267fa17ce3a91f59793045f055e | Extreme dose rate proton therapy - reducing side effects for brain cancer treatments. | The Brain Tumour Charity | Harvard University | HRCS22_14355 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public |
gen_7bd2a94c34c915271a4d213bd6be0888 | Establishing the content coverage of available Patient-Reported Outcome (PRO) measures used in neuro-oncology and provide recommendations on the use of these PRO measures: part of the Response Assessment in Neuro-Oncology – Patient Reported Outcome (RANO-PRO) initiative | The Brain Tumour Charity | Leiden University Medical Center | HRCS22_14356 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public |
gen_d30103d4cf44ae1c9eed9399fda6f394 | fASt and Smart charging solutions for full size URban hEavy Duty applications | European Commission | D'APPOLONIA SPA; RUPPRECHT CONSULT - FORSCHUNG & BERATUNG GMBH; TOFAS – Turk Otomobil Fabrikasi A.S. | CORDIS-769850 | The ASSURED Project proposal addresses the topic GV-08-2017, “Electrified urban commercial vehicles integration with fast charging infrastructure” of the Green Vehicle work programme. A 39-member consortium from 12 different EU Member States will conduct the work. The overall objectives of ASSURED are: - Analysing the needs of the cities, operators and end-users to derive the requirements and specifications for the next generation of electrically chargeable heavy-duty (HD) vehicles (i.e. buses), medium-duty (MD) trucks and light duty vehicles for operation within an urban environment; - Improving the total cost of ownership (TCO) through better understanding of the impact of fast charging profiles on battery lifetime, sizing, safety, grid reliability and energy- efficiency of the charger-vehicle combination; - Development of next generation modular high-power charging solutions for electrified HD and MD vehicles; - Development of innovative charging management strategies to improve the TCO, the environmental impact, operational cost and the impact on the grid stability from the fleet upscaling point of view; - Demonstration of 6 electrically chargeable HD vehicles (public transport buses), 3 MD trucks (2 refuse collections & 1 delivery truck) and 1 light duty vehicle with automatic fast charging; - Development of interoperable and scalable high power charging solutions among different key European charging solution providers; - Demonstration of energy and cost efficient wireless charging solutions up to 100 kW for an electric light duty vehicle (VAN); - Evaluating the cost, energy efficiency, impact on the grid of the different use cases, noise and environmental impact of the ASSURED solutions; - To actively support the take‐up of business cases and exploitation of project results across Europe of the use cases by partner cities (Barcelona, Osnabruck, Goteborg, Brussels, Jaworzno, Munich, Eindhoven, Bayonne, Madrid) and end users. | H2020-EU.3.4. / 3.4 Societal Challenges - Transport | 6project_grants_public |
gen_3d7a488a964f455d75f7e6a9d1587f75 | Baseline pathology image analyses by deep learning approaches to predict the onset of ESR1 mutations, an exploratory study on samples collected in PADA-1, a UCBG/GINECO phase 3 trial | Worldwide Cancer Research | Institute Curie | HRCS22_14403 | Background Pathology image analysis by deep neural networks has been successfully applied to the detection of numerous mutations (EGFR in NSCLC, BRCA…) already present in tumor cells; these approaches have however never been used to predict whether a resistance mutation will appear later during therapy. Mutations in ESR1, the gene encoding for estrogen receptor (ER) alpha, are rare (<5%) in untreated ER+ HER2- metastatic breast cancers before therapy but are “acquired” in ~40% of cancers as a mechanism of resistance to aromatase inhibitors (AI). Interestingly, these mutations are sensitive to selective ER degraders (SERDs). Predicting which cancer is more likely to develop an ESR1 mutation could transform ER+ breast cancer care, as it will allow targeting high-risk patients and even guide the use of SERDs before ESR1 mutations become detectable. Challenge We hypothesize that digitalized and combined hematoxylin-eosin (H&E), ER and PR (progesterone receptor) immunohistochemistry (IHC) analyses of pre-treatment tumor tissue by deep neural networks could accurately predict the later onset of ESR1 mutations during AI-based therapy. Methods 588 tumor samples, obtained with each patient consent before the start of first line AI + palbociclib therapy, have been collected as part of the PADA-1 trial (PI: FC Bidard; NCT03079011). These samples are fully annotated: patient and tumor characteristics, treatment response, PFS, OS and ESR1 mutation status by ctDNA analysis collected every 2 months during therapy, until tumor progression. Centralized H&E stained slides, ER and PR IHC slides will be digitalized and then processed by our deep learning Multiple Instance Learning workflow, based on tiling, encoding, attention scoring, tile aggregation, and slide classification. Deliverables We will establish validated algorithm predicting the individual risk to develop an “acquired” ESR1 mutations while on AI + Palbociclib. The prediction of treatment outcomes (PFS, OS) will also be assessed as a by-product of this analysis. | 6.1 Pharmaceuticals | 6project_grants_public |
gen_1e5e056f4f6379cf489de6387a835933 | Music, Performing Arts and Artists in the North: The French and Italian Diasporas (1600-1900) | Carlsberg Foundation | Det nationalhistoriske Museum, Frederiskborg Slot and Château de Versailles | CF18-0357 | Not available | Research / Conferences / Award | 6project_grants_public |
gen_9e61d146a48b9c42163a5f163a14e969 | Modelling neuroblastoma - immune cell interactions in a tissue- engineered 3D platform | Neuroblastoma UK | Royal College of Surgeons in Ireland | HRCS22_14420 | Combining 3D printing with cancer research | No Research Activity assigned | 6project_grants_public |
gen_d0acd25723dd0053dcc54bafa035ce92 | Making the invisible visible: In vivo mapping of molecular biomarkers in adult diffuse glioma with CEST MRI | The Brain Tumour Charity | Erasmus MC | HRCS22_14464 | No abstract available for this analysis. | No Research Activity assigned | 6project_grants_public |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
gen_b066d104cf26b0ee28e34921439b4a88 | Prioritisation and Risk Evaluation of Medicines in the EnviRonment | European Commission | Eli Lilly and Company Ltd; F. Hoffmann-La Roche AG | CORDIS-875508 | There are around 1900 active pharmaceutical ingredients (APIs) in use, yet the environmental risks of only a small proportion of these has been assessed. This calls for pragmatic science-based approaches for prioritising existing APIs in terms of their environmental risk. Such approaches could also be used pro-actively, i.e. to identify environmental concerns earlier in the drug development process, thereby contributing to a more sustainable future. The overall aim of PREMIER is to deliver an API information and assessment system for characterising the potential environmental risks of APIs, including relevant human metabolites and environmental transformation products, based on minimal testing. This system will be designed to screen and prioritise legacy APIs for tailored environmental assessment; identify potential environmental hazards associated with APIs in development; and to make the available environmental data more accessible for all stakeholders. The system will be optimized and validated using case studies on approximately 25 APIs. PREMIER will realize its aim by combining world-leading research on the environmental risks of APIs with the principles of co-design and smart knowledge-based IT. Through this combination, we want to be more than a conventional research project. We want to ensure that the results of our ground-breaking research “work” address all the societal concerns about the potential risks posed by the presence of pharmaceuticals in the environment. | H2020-EU.3.1. / 3.1 Societal Challenges - Health | 6project_grants_public |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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)_x0001_Optimization of lead molecule “COCH c.151C>T ASO-E”. 2)_x0001_Evaluation of molecule efficacy in DFNA9 patient-specific inner ear cells. 3)_x0001_Delivery and biodistribution of ASOs in the mammalian cochlea and vestibular system 4)_x0001_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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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 |
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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