NIHRDataInsights/HRCSData huggingface dataset:
Award Title: Early diagnosis and Personalised therapy for myelodysplastic syndromes
Funder: Cancer Research UK

Abstract: Background
Recent studies from cohorts of individuals with normal blood counts have shown that acquisition of clonal haematopoiesis is common with aging. Importantly, genetic aberrations found in such individuals mirror those seen in myelodysplastic syndrome (MDS), a haematopoietic cancer affecting 5000 individuals in the UK, characterised by low blood counts and transformation to acute myeloid leukaemia (AML). The presence of subclinical clonal haematopoiesis (“clonal haematopoiesis of indeterminate potential”,CHIP) confers a
10-15-fold increased risk of MDS or other haematopoietic cancer, rising to 50-fold if variant allele frequency exceeds 10%. Notably, treated MDS/AML patients retain such clones with or without additional genetic abnormalities, following conventional treatment. Thus clonal haematopoietic stem and progenitor cells (HSPC) appear to serve as founder clones that can evolve to MDS and these clones are stable and resistant to current treatments.
A central question driving this proposal is how and when does CHIP transition to MDS/haematological cancer? If patients most at risk of cancer could be identified, they could be prioritised for early follow-up and therapeutic strategies. In patients diagnosed with MDS, a wide range of clonal heterogeneity exists at presentation and throughout treatment. This co-existent clonal genetic variegation suggests that MDS driver mutations have a range of cellular behaviours that may also depend on epigenetic or micro-environmental factors. Identifying genotypic and phenotypic determinants of clonal dominance will permit prioritisation of pathways for further therapeutic targeting.

Objectives/Methods
1. To undertake in vivo drug screens in zebrafish to define small molecules that selectively deplete haematopoietic stem and progenitor cells (HSPC) carrying MDS-associated mutations
2. To understand the clonal heterogeneity of MDS, and the impact of both genotypic and phenotypic variation in mutated haematopoietic cells in driving the evolution to AML
 3. Define and quantify the utility of CHIP as a biomarker for the development of MDS (and other haematopoietic malignancies)

 How the research will be used
Objective 1 will identify known drugs that have been validated in murine xenografts that can selectively kill HSPC with MDS/CHIP mutations. These compounds will be used for future mechanistic/drug development opportunities
Objective 2 will provide a comprehensive understanding of the cell autonomous clonal dynamics of MDS. Future therapeutic strategies will be defined using genotype combinations, and transcriptional phenotypes that lead to MDS.
Objective 3 will define the natural history of evolution of CHIP to haematopoietic malignancy and identify methods to stratify those patients at greatest risk of malignancy using CHIP as a biomarker.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS;BLOOD
Award Title: East London Genes & Health: human knockouts in a population genomic medicine cohort of British-South Asians
Funder: Wellcome Trust

Abstract: East London Genes & Health is a long term programme for population genomic medicine research in British-South Asian adults. Unique features include high rates of health deprivation, especially diabetes, cardiovascular disease and mental health; high rates of consanguinity (including human knockouts, rare predicted loss of function variants occurring as homozygotes); local excellence in e-health record access/analysis; and recall for further research by genotype/phenotype.
 
 
 
 In this proposal we wish to continue and expand successful East London Genes & Health recruitment and commence a new site Bradford Genes & Health - to reach 100,000 volunteers; add value to the Genes & Health resource through SNP array genotyping all samples; and by sequencing and analysing consanguineous individuals. This will then enable us as a collaborative team to ask detailed research questions about adult-human knockouts. Specifically we will perform population based analyses of naturally occurring adult-human knockouts to better understand their population genetics, and (with Deciphering Developmental Disorders) recessive disease; contribute to and establish The Human Knockout Project, a worldwide database of population-based studies of human knockouts; perform blood -omics to study major perturbations of biological systems including downstream networks; and deeply study individuals with knockouts and other variants in reported Mendelian disease genes.

Lay Abstract: East London Genes  &  Health is a long term programme of health research in British-South Asian adults. Unique features include high rates of poor health, especially diabetes, cardiovascular disease and mental health; high rates of related parents (leading to naturally occurring ‘human knockouts’, inactivating genes); excellent electronic health record data on volunteers; and recall of volunteers for additional research studies.

 

  We wish to expand successful East London Genes  &  Health recruitment and commence a new site Bradford Genes  &  Health, to reach 100,000 volunteers. We will analyse the genes of all volunteers to look for known genetic variants, and sequence the genes of those with related parents to find rare coding variations in genes. With this information we can ask research questions about human ‘knockout genes’ including how they affect populations, biological systems and networks, establishing a worldwide database including health data, and a better understanding of recessive human disease.

Research Activity Codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health Categories: MENTAL HEALTH;METABOLIC AND ENDOCRINE;CARDIOVASCULAR;GENERIC HEALTH RELEVANCE
Award Title: Effects of natural and urban environments on human stress and function
Funder: The British Academy

Abstract: The overwhelming majority of the human evolutionary journey was spent in natural environments. Consequently, nature provided the parameters within which natural selection has acted to shape the physiology of our species. However, the last 200-300 years has seen mass migration to urban centres. The replacement nature’s forests, plains, coastlines and mountains with alien cityscapes has created a mismatch between our nature-adapted physiology and the highly-urbanised world many of us inhabit today. As predicted by evolutionary theory, this mismatch has led to chronic stress. The stress-reducing effects of spending time in natural environments are well documented. Importantly, it remains unknown how our environment impacts key functions essential to survival; namely immune, cognitive and physical function. Using an experimental protocol, we will assess whether stress and functional capabilities differ between natural and urban environments. The results will increase understanding of how natural ancestral environments influence humans navigating today’s urban world.


Research Activity Codes: 3.2 INTERVENTIONS TO ALTER PHYSICAL AND BIOLOGICAL ENVIRONMENTAL RISKS
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Efficacy of Mirococept (APT070) for Preventing Ischaemia-Reperfusion Injury associated with Kidney Transplantation-2 (EMPIRIKAL-2)
Funder: Medical Research Council

Abstract: Delayed graft function (DGF) is a manifestation of  ischaemia-reperfusion injury (IRI) and has a deleterious effect on the lifespan of the graft and the patient. We are seeking to define a therapeutic approach for the prevention of IRI to the kidney during the period immediately after transplantation.  This damage is linked to activation of the complement system that occurs through recognition of the grafted organ as foreign and/or damaged, as shown in a MRC funded programme of work. We have approached this problem firstly by engineering a recombinant form of a human complement-regulatory molecule known to be present in the normal kidney at low density and secondly by modifying this molecule so that it can be delivered to the graft by perfusion before transplantation and retained within the kidney at increased density during the period that damage is thought to occur. Preclinical and exploratory clinical studies have indicated that this approach is safe and has the potential to reduce the incidence of DGF in renal transplantation. A Phase IIb dosing/efficacy study has completed the first cohort of 80 patients, the results of which indicate the need for dose escalation. We are now seeking to extend the study using a revised design based on the results of a new dose escalation study in isolated pig kidneys. The revised clinical design involves two stages: Stage 1, a Phase II dosing/efficacy study (for which funding is presently sought); and Stage 2, a Phase III confirmatory study (for which no funding is sought at the present time). This design will enable us to reach a satisfactory endpoint with a smaller number of patients than the original trial. The study will show whether treatment of the donor kidney with the engineered construct lowers the incidence of DGF and improves the mid-term function of the graft.


Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: RENAL AND UROGENITAL
Award Title: Electron tomography of prokaryotic cell surfaces
Funder: Medical Research Council

Abstract: My laboratory uses electron tomography, combined with several structural and cell biology techniques, to study cell surfaces of prokaryotes at the atomic level. Surface molecules mediate all cellular interactions with the environment and play important roles in important processes including cell adhesion, biofilm formation and antibiotic tolerance in pathogenic bacteria.  Our research aims to push the boundaries of cellular structural biology, with technical developments aimed at identifying molecules on cell surfaces, and resolving their high-resolution details on prokaryotic cells. While structural biology of many cell surface molecules reveals fundamental information about bacteria and archaea, or work has clear biomedical relevance, since surface molecules allow pathogenic bacteria such as P. aeruginosa to evade antibiotics and infect humans by forming biofilms.


Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: GENERIC HEALTH RELEVANCE;INFECTION
Award Title: Elucidating molecular determinants of Trypanosoma cruzi persisters.
Funder: Medical Research Council

Abstract: Quiescent, less-drug susceptible T. cruzi parasites pose a key challenge for Chagas disease drug discovery. There currently is no understanding of these persister forms at the molecular level. Here, I propose to use single-cell RNA-sequencing (scRNA-seq) to, for the first time, reveal population heterogeneity in the intracellular amastigote population and to characterise the persister parasites through their gene expression profile. For this I will employ drop-seq technology on methanol-fixed parasites, including the complete intracellular parasite population isolated from mammalian host cells and populations enriched for persisters through fluorescence-activated cell sorting. Expression level differences will be validated both at the mRNA and protein level. The transcriptome data will dramatically increase our understanding of persisters and allow identification of persister markers. To demonstrate physiological relevance of the in vitro persisters, I will use the identified marker genes to probe for persisters in tissues from infected mice. Finally, I propose a large high-content screen with 130,000 compounds to identify compounds that can promote either entry or exit from the persister state. The high-throughput screen will be based on previously demonstrated dye-retention as a persister marker, whereas validation will be carried out with the persister markers found through scRNA-seq. Compounds that stimulate persister replication will be tested in combination with compounds known to kill replicative parasites in intracellular viability assays to test this type of combination as an new treatment approach. Overall this work will provide key information regarding T. cruzi population heterogeneity and the nature of T. cruzi persisters and will enable further research into the fundamental biology of persisters as well as support drug discovery efforts allowing creation of better assays, specific detection of persisters and rational identification of drug targets.


Research Activity Codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health Categories: INFECTION
Award Title: Elucidating the role of sleep in FTD and AD: from neurons to networks in vivo
Funder: Medical Research Council

Abstract: Sleep disturbance is common to several progressive dementia-related illnesses. As well as affecting cognition, sleep impairment has also been recently implicated in pathological protein accumulation and neurodegeneration, suggesting that sleep may be a promising treatment target for dementia. Nevertheless, defining and realising the potential of sleep-targeting therapies requires a more complete understanding of the most relevant disease-specific sleep phenotypes. Brain activity during normal sleep is characterised by circuit-specific brain oscillations that play a key role in memory and learning, and a major open question concerns how such brain activity is dysregulated in major dementias such as Alzheimer’s Disease (AD) and frontotemporal dementia (FTD), and the underpinning disease-specific markers of neuronal dysfunction. Here, using an innovative approach involving both rodents and humans, I will examine how FTD and AD affect sleep electrophysiology measures that reflect underlying disease effects on sleep neurobiology. I will assess sleep in a cohort of well-characterised gender and age-matched (behavioural-variant) FTD and amnestic-AD patients (identified through the Queen Square Specialist Cognitive Disorders Clinic), and healthy controls (N = 5/group), using electroencephalography (EEG headbands) in the home environment. I will further perform parallel electrophysiology (multi-channel NeuroPixels) experiments in mouse models of AD and FTD to characterise disease-specific neuronal dysregulation that underlies impaired sleep oscillations. Finally, I will design and test novel auditory stimulation paradigms that are aimed at restoring impaired brain oscillations. These pilot data will form the basis for a larger clinical study assessing the potential of this intervention to enhance sleep oscillations in AD and FTD patients, with the ultimate aim to improve cognitive-behavioural function and delay disease progression.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health Categories: NEUROLOGICAL
Award Title: Enabling advance imaging of synaptic function in living males and females over the course of the life-span with Positron Emission Tomography (PET)
Funder: Wellcome Trust

Abstract: Synapses are damaged in over 130 different brain diseases and yet thus far there are no reliable ways to measure synaptic structure or function in vivo in a preclinical or clinical setting. The recent discovery of promising Positron Emission Tomography (PET) radiotracers for imaging synapses, by targeting the synaptic vesicle glycoprotein 2A (SV2A), has the potential to transform clinical diagnosis, neuropathology, drug development and treatment of multiple brain diseases. Two major bottlenecks to deliver on this promise are: (1) the unavailability of high-yield and high-molar activity [18F]MNI1126, the lead SV2A PET radiotracer; and (2) the lack of a quantitatively accurate and validated SV2A brain PET atlas during normal aging in rodent models. This project will generate synthetic routes and radiochemistry methods for efficient production of [18F]MNI1126, it will develop detailed template resources for quantitative analysis of SV2A PET signal in different brain regions over the course of natural aging in the rat and mouse, and it will validate SV2A PET in vivo outcomes at unprecedented scale and resolution using synaptome mapping technology. The development of SV2A PET technology proposed in this award will catapult the use of quantitative SV2A PET in many brain diseases in humans and model organisms.

Lay Abstract: Synapses are the connections between the nerve cells in the brain and they are essential for all our thoughts and actions. Synapses are damaged in most brain diseases and until recently there were no tools for monitoring them in the living brain. Researchers discovered a synthetic small molecule that can be used to monitor synapses in humans and animals. When injected, the molecule binds to the synaptic protein SV2A, which can then be detected using a brain imaging approach used in the clinic called Positron Emission Tomography (or PET). This project aims to develop this SV2A PET tool so that it can be used to better understand how the brain works during health and disease, to better diagnose patients and to discover new medicines to treat brain diseases.

Research Activity Codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: MENTAL HEALTH;NEUROLOGICAL
Award Title: Enabling imaging of cells and tissues across scales
Funder: Wellcome Trust

Abstract: We seek funding for an array tomography scanning electron microscope (SEM) with ATLAS 5 software together with components to upgrade an associated light microscope, to enable 3D correlative light and electron microscopy (CLEM) of cells and tissues with nm resolution. Array tomography SEM allows for the detection, mapping and automated imaging of serial sections of resin embedded samples and is non-destructive technology.   This technology is transformative and will enable high resolution 3D correlation of molecular machineries with cellular structure and specific cell and tissue processes. Using this new technology, our initial consortium of PIs will address the following specific objectives:    1.  To elucidate the mechanism of 3D patterning during organogenesis (Pichaud)   2.  To characterise the fundamental principle that regulate intracellular trafficking of cargoes and membrane, storage and lysosomal degradation (Brodsky, Futter and Schiavo)   3.  To determine the molecular basis for the interaction between the HIV virus and its host cells and tissues (Jolly and Marsh)   4.  To elucidate the fundamental mechanisms of nuclear remodelling during passage through mitosis (Baum)  5.  To elucidate the connectivity underlying circuit function (Hausser and Wilson)   Altogether, our proposed studies will elucidate fundamental mechanisms of cell and tissue morphogenesis, homeostasis, function repair and infection.

Lay Abstract: Correct cell function depends on the successful interaction between molecular machineries, which support critical tasks such as the transport of molecules in and out of the cell, the ability for cells to respond to their external environment, and ensure cells maintain the right shape. Yet cells do not usually function alone but exist as part of a collective, making up organs and tissues. Thus, to effectively study cells we must take into account both their molecular machineries and their environment, requiring us to move seamlessly from the microscopic to the macroscopic, examining cells across spatial scales. This is not trivial, as the technologies required to study molecules are different from those used to study whole cells and groups of cells. The new microscope we will acquire with this funding will bridge this gap by allowing us to overlay molecular information onto cellular structures and within cell collectives.

Research Activity Codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Enriching Engagement Extended Pilot: Oxford's Institutional Research Engagement Fund programme
Funder: Wellcome Trust

Abstract: This proposal is to extend the initial Oxford Enriching Engagement pilot scheme (Institutional Research Enrichment Fund award 217077/Z/19/Z, 2019-2020) for devolved Wellcome Research Enrichment: Public Engagement funding.
 
This extended pilot programme will build on, enhance and enrich the significant work that has already taken place to further increase the effectiveness and dynamism of this scheme to achieve the desired outcomes.
 
Enriching Engagement will continue to support a diverse range of Wellcome-funded researchers to apply for, and if funded deliver, high-quality PER activities that result in tangible positive changes and outcomes, drawing upon the expertise of Oxford's PE staff.
 
This extended pilot will also enable an increase in evidence to be gathered on outcomes, successes, challenges and lessons learnt from this approach across the whole pilot period (which, if this extension is funded, will be April 2019 - December 2021) and gather medium and longer term outcomes from the initial pilot phase.
 
This learning has the potential to shape future engagement funding mechanisms and inform other institutions and networks on running their own devolved funding schemes - the latter has the potential to significantly increase the effectiveness and efficiency of these institutions' plans from the get-go, therefore offering significant added-value.


Research Activity Codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health Categories: GENERIC HEALTH RELEVANCE
Award Title: Epidemics Ethics
Funder: Wellcome Trust

Abstract: With this proposal we seek to establish a global community of bioethicists (to be known as 'Epidemics Ethics') combined with a range of online resources and activities together capable of providing real-time, contextually appropriate support to assist researchers, policy-makers, communities, and responders in identifying, analysing and addressing ethical issues arising in the context of global health emergencies. Epidemics Ethics will complement the newly established Public Health Emergency Preparedness and Response Ethics Network (PHEPREN) by providing: timely responses to ethical problems, access to networks of experts, an array of online resources including seminars, workshops, blogs, and ethics briefings on issues of current concern. A key aim of Epidemics Ethics will be to support the establishment of fair, collaborative partnerships to enable ethics research to be conducted by ethics scholars in low and middle-income countries in the context of broader supportive international collaborations. With this in mind, capacity building will be a key focus.


Research Activity Codes: 8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health Categories: GENERIC HEALTH RELEVANCE