NIHRDataInsights/HRCSData huggingface dataset:
Title: Reconstructing a Gene Regulatory Network for cell fate decisions in the sensory nervous system
Funder: Wellcome Trust

Abstract: The nervous system is the most complex organ in our body with thousands of different cell types. How is such diversity generated? This remains one of the key questions in developmental biology, which ultimately will inform regenerative medicine and cell reprogramming. Single cell technologies have shed light on how progenitor cells may commit to a particular fate, challenging the long-standing assumptions that cell differentiation is a smooth, continuous process.This project will dissect the molecular mechanisms controlling how progenitors give rise to different cell types in the sensory nervous system of the vertebrate head. Despite a wealth of information on signalling, cell movements and timing of this process, a mechanistic understanding of how progenitors diversify is still missing. This is therefore an ideal context to apply a systematic, single-cell approach to identify and characterise cell fate decisions.I will obtain single cell gene expression and chromatin state data from the developing chick embryo and use this to predict developmental trajectories, branchpoints, and candidate transcription factors regulating these branch points. I will then use perturbation analysis to validate these predictions. Together, this will reconstruct the molecular circuitry, the gene regulatory network, that drives cell fate decisions in the sensory nervous system.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS;NEUROLOGICAL
Title: Using Artificial Intelligence to Leverage Proteomics Data for Stratified Medicine
Funder: Wellcome Trust

Abstract: Stratified medicine, in which information from a patient’s genome is used to help direct their treatment, has revolutionised some areas of clinical practice. However, most diseases do not involve changes in an individual’s genome, so the power of insights derived from genotyping and whole genome sequencing is limited. Interrogation of a patient’s proteome (the collection of 20,000+ unique proteins that can be extracted from human tissue and body fluids) promises much more fine-grained insight into the state of a patient, because proteins are the key functional molecules of biology. The abundance, location, physical structure and activity of each protein can vary substantially during disease progression, providing a wealth of information for assessing a patient’s state and forming a treatment plan. But how to reliably turn proteomic data into clinical insights remains an open question. This project will investigate the extent to which artificial intelligence (AI) can be used to leverage proteomics data for stratified medicine. This will be achieved by applying cutting edge data science and AI techniques with the aim of producing reliable and explainable readouts of disease state from clinical proteomics data, overcoming inherent challenges in these data such as heterogeneity, missingness and lack of statistical power.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS;NEUROLOGICAL
Title: King's Innovations Translational Partnership Award
Funder: Wellcome Trust

Abstract: The King's Wellcome Innovations Translational Partnership Award (ITPA) will enable us to exploit the full potential of King's outstanding biomedical research to produce improvements in health and economic benefit. It will build on substantial investments in translational infrastructure (including through two NIHR Biomedical Research Centres) to up-skill our academic community, to provide a specialist source of guidance and support, and to provide funding to accelerate intellectual property development and protection. Our research strengths are focused in the areas of advanced therapies, healthcare engineering, neuroscience and mental health, and physiological medicine (cardiovascular, immunology, cancer). The ITPA will support the development of a programme of activities cutting across these areas: • King's Translational Academy: a new training programme to provide members of our academic community with core translational knowledge/skills, and to signpost key facilities/sources of expert support. • Translational Research Office: a new, dedicated team of experienced translational support staff, to provide individual support to academics planning and undertaking translational research. • Commercial Development Fund: a new, responsive pump-priming/development fund to strengthen IP, and undertake detailed planning to understand healthcare pathways and commercial opportunities. These activities will work in synergy with existing translational support and seed funding programmes to enhance our translational ecosystem.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS;NEUROLOGICAL
Title: Gurdon Institute Centre Extension
Funder: Wellcome Trust

Abstract: Our vision is to understand the fundamental mechanisms of normal development, to determine how these mechanisms are subverted in cancer and other diseases, and to apply this knowledge to develop new therapies. Our research themes focus on: cell proliferation and genome maintenance; function and regulation of the genome and epigenome; mechanisms of cell fate determination, multipotency and plasticity; and the cell biology of organ development and function. We also emphasize two strategic directions: (i) human development and disease and (ii) quantitative analysis of cellular dynamics, to understand developmental and disease processes quantitatively at the molecular, cellular and tissue scales. We investigate both normal development and disease in a range of in vivo model systems, as well as primary human tissues, organoid systems, and patient-derived stem cells. Extension funding would allow us to further progress our overall scientific vision, our strategic areas of human development and quantitative approaches, our work on in vivo models of disease, and the translation of our research. It would also support our ambitious public engagement programme, enable continuation and development of our training activities, and underpin our efforts towards and commitment to a positive and inclusive research culture.


Research activity codes: 1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING)
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS;NEUROLOGICAL
Title: Cambridge Stem Cell Institute
Funder: Wellcome Trust

Abstract: Stem and progenitor cells are essential for the maintenance of metazoan tissues. Their dysfunction underlies diverse human diseases and their manipulation provides enormous therapeutic possibilities. The Cambridge Stem Cell Institute (CSCI) is a world-leading centre for stem cell research. Its mission is to transform the prevention, diagnosis and treatment of disease through a deep understanding of the mechanisms regulating stem and progenitor cells, both normal and pathological. In 2018 CSCI investigators will come together in a new purpose-built building on the Cambridge Biomedical Campus adjacent to Addenbrookes Hospital. A key strategy is to embed biological, clinical and physical scientists operating across disparate tissues and at multiple scales, thus allowing commonalities and differences to be explored in an cohesive and inter-disciplinary manner. A network of affiliated PIs will provide bridges to basic and disease-focused institutes throughout Cambridge and will ensure that CSCI represents the heart of a vibrant stem cell community. Importantly a critical mass of clinician scientists will create synergistic interactions between basic scientists and those driven by disease-focused questions, thus ensuring that CSCI is fully integrated with its clinical environment and empowered to pursue its translational goals.

Lay abstract: No Data Entered

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS;NEUROLOGICAL
Title: A ‘Dark Genome’ analysis suite / Division of Psychological Medicine and Clinical Neurosciences (DPMCN)
Funder: Welsh Government Office for Science

Abstract: The ‘Dark Genome’ analysis suite will support future academic research, clinical diagnostics and commercial enterprises in genomics of health and disease in Wales. This will include the development of improved protocols for the clinical testing of genetic variants, such as those for repeat expansions in neurological disorders and chromothripsis in cancer,


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS;NEUROLOGICAL
Title: The function of the imprinted microRNA-483 in growth, metabolism and cancer
Funder: Medical Research Council

Abstract: Growth is essential for life. Regulation of growth of an organism in relation to its environment is pivotal for evolutionary success and fitness. Related and similarly important is the regulation of the size of the individual organs in the body in relation to each other and to the size of the whole organism. The pathway in which the Growth Hormone/Insulin-like growth factor 1 axis participates provides the main conduit of growth control as evidenced by mouse genetic experiments. It is estimated that only 17% of the total body size of an adult mouse can be attained without the participation of GH and IGF1. Finding growth control mechanisms that are independent of the circuitry involving GH/IGF1 is an important basic research topic, with important clinical applications. MicroRNAs are a large family of post-transcriptional regulators of gene expression that are ~21 nucleotides in length. A single miRNA may act as a master control of gene expression through regulation of multiple targets. Up to a third of microRNA genes are intronic and transcribed along theirs host genes. The major fetal growth factor IGF2 locus harbors a microRNA (miR-483). We recently tested the potential activity of miR-483 as a growth control microRNA by generating a knock-out mouse. Our results provide evidence for an important role of miR-483 in early postnatal body size and organ growth control. To our knowledge miR-483 constitutes the first example of a growth control miRNA. This proposal aims to seek the molecular pathways underlying growth repression by miR-483. We will explore the idea that miR-483 may interfere with previously undescribed genetic pathways that control growth. This work will yield important novel insights into the genetics of growth and cell proliferation diseases such as cancer, in addition to contributing to our understanding of the evolution of genomic imprintin


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;CANCER AND NEOPLASMS;REPRODUCTIVE HEALTH AND CHILDBIRTH;METABOLIC AND ENDOCRINE
Title: Developmental dynamics of the epigenome
Funder: Biotechnology and Biological Sciences Research Council

Abstract: This Theme examines in detail the mechanisms and genome-wide dynamics of reprogramming and programming events in GCs and early embryos, in tissues during ageing as well as the biology involved. It builds directly upon the resource established in Theme 1, and adds value to it. It also involves analysis of additional epigenomes, e.g. in conditional knockouts or transgenics of epigeetic modifiers. The objectives are to determine the mechanistic basis of: (1) epigenetic reprogramming in PGCs, (2) programng in later stage GCs, (3) reprogramming in early embryos (4), programming during early lineage commitment to ICM, TE, and PE, and derived stem cells (5), imprinting and transgenerational inheritance (6,) Influence of ageing upon the epigenome of the non-replicating genome of cardiac myocytes and effects thereof upon cardiac adaptation.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CARDIOVASCULAR
Title: Dynamic clinical risk predictions in personalised medicine: development and application of joint models for repeatedly measured biomarkers and time-to-event data in biomedical research.
Funder: Department of Health (England)

Abstract: Joint models of longitudinal data, such as repeatedly measured blood pressure, and survival data, such as time to death, can be used to develop dynamic risk predictions tailored to individual patients. This project aims to develop methodological aspects of joint modelling for use in multiple applied projects, including novel applications to linked national registry datasets. Analyses will be undertaken investigating the effects of jointly modelling biomarker data, such as blood pressure and cholesterol, and time to clinical events, such as stroke or myocardial infarction, with the direct goal of improving risk prediction models. In parallel, user-friendly software will be developed.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: GENERIC HEALTH RELEVANCE;CARDIOVASCULAR
Title: Optical Cannula: Development of a tool for studying the inside of tubular organs under physiologically relevant conditions by imaging from within
Funder: Wellcome Trust

Abstract: Building on our recent imaging advances (refs-1-4), we will develop an optical platform to provide imaging access inside blood vessels and "hollow organs" (<150&mu;m to 1mm diameter)with dramatically improved image clarity and large-scale of visualization in a physiological configuration by imaging from within. Advanced confocal and widefield microscopy techniques will be combined with focus-locking and adapive field-curvature correction to facilitate large-field (hundreds of cells) high-resolution imaging of the deepest, hard to access, layers of blood vessels, overcoming the small image fields, and imaging aberrations associated with conventional approaches. Automated data collection and analysis will provide high throughput ex vivo imaging in a physiologically intact manner not previously possible. Validating our technology in both our labs, and those of our project partners, we will iteratively refine and develop our platform for use on all pathological conditions linked to cardiovascular disease, and explore uses with other tubular organs. Wider dissemination of our platform will be assured through open access portals. Our project will deliver organ scale, physiologically relevant high resolution and high speed imaging, integrated data extraction and high-throughput analytical capacity. These breakthroughs will stimulate new understandings of cardiovascular disease with immediate impact on biomedical investigations.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;1.5 RESOURCES AND INFRASTRUCTURE (UNDERPINNING);1.3 CHEMICAL AND PHYSICAL SCIENCES;1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CARDIOVASCULAR
Title: Unravelling the physics of the pressure drop in blood flow constrictions
Funder: Wellcome Trust

Abstract: This programme will engage with those living with cardiac conditions to understand their stories and empower them to co-create a sensory and interactive journey through our heart. Together, we will deliver an immersive and interactive ‘inside the heart’ experience, an overall poetic and memorable experience for our target audiences to understand the power of the flow, and why blood flow is a major element determining our cardiovascular health. Building on our success of the “Big Heart Data” exhibition at Science Gallery London, the collaboration with designers, artists and charities will be the key to deliver this experience. We will collaborate with those living with cardiac conditions to help shape the exhibit and also our ideas on the future of healthcare enabled by computer models. We will inspire young students by illustrating the powerful role imaging and computer technologies play in improving heart healthcare. The finale of the collaboration will be an exhibit at the London Design Festival, followed by a touring of the exhibit alongside workshops with target audiences where they will get to discuss the exhibit and the science behind it with the scientists and designers themselves. This project will enable the research team led by Pablo Lamata to gain a better understanding of how heart patients think and feel about the research, plus establish a new perspective through working with Cellule studio. The team will further develop their public engagement practice and improve their confidence in engaging various audiences.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: GENERIC HEALTH RELEVANCE;CARDIOVASCULAR
Title: Exploring the Molecular Mechanisms and Physiological Role of pH Sensitive Chloride Channels in the Vasculature
Funder: Wellcome Trust

Abstract: Blood vessels, including arteries and capillaries, are equipped to constrict and dilate in response to changes in their environment. Importantly, vessels are known to respond to pH. A key example is in the lungs, where lung damage prevents these regions from taking up oxygen, making the area hypoxic and acidic. This causes vessels in the damaged area to constrict, reducing blood flow. However, the ways by which vessels respond to pH are not fully understood. Recently, the gene encoding a pH-sensing protein named PAC has been identified. PAC is an ion channel, forming a gated pore in cell membranes which opens in response to acidic pH and allows movement of chloride ions. Here we propose that PAC is important for vessels to respond to acidity. We will investigate this by measuring chloride currents in vascular cells, and by using a technique called myography which allows us to observe vessel constriction. We will apply these techniques to study channel structure, and explore potential drugs which target the channel. Overall, this will further our understanding of how blood vessels respond to pH. The long-term goal is enabling PAC to become a target for diseases of the lungs and other organs.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;CARDIOVASCULAR
Title: The Epicardium as the Conductor of Cardiovascular Cells in Cardiac Regeneration
Funder: Wellcome Trust

Abstract: Regenerative cardiovascular medicine is emerging as a novel therapeutic alternative to heart transplantation in patients suffering from chronic heart failure. This approach aims to restore cardiac functionality by exogenous transplantation of stem cell-derived cardiomyocytes. Although promising, challenges to cardiac repair remain, for example with respect to cell maturation and revascularisation. It has recently been shown in rats, that these challenges can be improved by co-transplantation of stem cell-derived epicardial cells. One plausible explanation for these improvements is paracrine-mediated effects. Paracrine signalling involves secretion of signalling factors in cells to alter the behaviour of surrounding cells, often in a gradient-dependent manner. Paracrine signalling factors include secreted proteins and miRNAs. They can be secreted into the extracellular space directly or packed into small extracellular vesicles, called exosomes. I aim to identify and characterise paracrine signalling factors of stem cell-derived epicardial cells, which promote myocardial maturation and vascularisation. Candidate paracrine signalling factors will be selected based on gene, protein, and miRNA expression and functionally characterised in vitro and in vivo. Identification of effective paracrine signalling factors will make it possible to address selected cardiac repair processes, resulting in new approaches to therapy.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: GENERIC HEALTH RELEVANCE;CARDIOVASCULAR
Title: The use of routine healthcare data in the development of efficient personalised medicine trials in heterogeneous critical care populations
Funder: Wellcome Trust

Abstract: I will use routine healthcare data to undertake feasibility work to inform novel clinical trial design and trial populations in heterogeneous populations. There is an unmet need for this in intensive care research. I will frame this around critically ill patients with CVD following on from my PhD, however this will be applicable to other disease/pathologies with heterogeneous populations. I hypothesise that critically ill patients with co-existing CVD may benefit from higher oxygen delivery to the myocardium during critical illness, preventing myocardial infarction and subsequent cardiovascular mortality. Key goals: 1. Identification of current outcomes for critically ill patients with CVD. I will link high quality Scottish routine healthcare datasets for all admissions to Scottish ICUs 2010-2018. I will characterise cardiovascular and non-cardiovascular outcomes and healthcare trajectories for these patients. 2. Identification of patients in whom CVD has the highest attributable mortality. This group would be the target population for a cardiovascular intervention trial. I will use prediction modelling, latent variable analysis and propensity score analysis to address this. 3. Identification of intermediate short-term outcomes using both routinely collected time series ICU physiological data, national datasets and existing trial datasets. 4. Development of efficient trial methodology, including Bayesian adaptive trial designs.

Lay abstract: Novel clinical trial design is needed to reduce the burden of research on patients, reduce costs, and improve efficiency. High quality routine healthcare data can help identify at risk groups and quantify important outcomes. This work is framed around critically ill patients with cardiovascular disease (CVD), following on from my PhD. Patients with CVD have a vulnerable heart muscle at risk of damage due to lack of oxygen. Interventions to increase oxygen delivery may benefit these patients. I will describe critically ill patients with CVD using data routinely collected in all Scottish hospitals. I will explore rates of cardiovascular events and mortality, and identify groups where the cardiovascular risk is greatest, and therefore where cardiovascular interventions are most likely to be beneficial. I will explore the relationship between routinely collected vital-signs data in ICU and longer-term outcomes, and I will develop my expertise in efficient trial methodology.

Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE;CARDIOVASCULAR