NIHRDataInsights/HRCSData huggingface dataset:
Title: Aetiology of donation-related health outcomes
Funder: Department of Health and Social Care

Abstract: This theme will address the NIHR BTRU mandate “to help identify and understand molecular and biological determinants of potential adverse consequences of donation in order to inform strategies to mitigate and/or prevent them”. 2.1: focus on: a) neurocognitive outcomes, ie, restless legs syndrome, pica, headache, dizziness b) cardiometabolic outcomes, ie breathlessness, palpitations, chest pain, glycaemia measures, lipids c) fainting episodes (both at donor sessions and delayed fainting episodes). Analysis of these outcomes has not already been funded because they are additions to the trial protocol. For continuous outcomes, we will compare mean values observed at the 2-year and subsequent surveys across different randomised intervention groups in the INTERVAL Trial (eg, 8-wk versus 12-wk intervals in men), with >90% power to detect differences of 0.055 SD or larger. For categorical outcomes, we will compare frequencies (prevalences) observed at the 2-year and subsequent surveys, again, across different randomised intervention groups, typically with >90% power to detect differences of 3% or larger. 2.2:characterise associations of baseline iron-related biomarkers by: a) quantifying relationships with health outcomes by correcting associations concurrently for regression dilution in exposures, when relevant b) defining the shapes of dose-response relationships with health outcomes, which, in the case of non-linear associations, may suggest the need for special Mendelian randomisation methods c) exploring whether the associations with outcomes vary in key subgroups (eg, by age and sex). 2.3: use results from Theme 1 to develop various powerful Mendelian randomisation tools (eg, multi-variant allele and GWAS scores) which should maximise variability explained in iron-related biomarker levels. We will develop tools that regard each of hepcidin, ferritin, and serum iron separately (“single marker Mendelian randomisation tools”)37 as well as multi-marker tools that capture their integrated effects on iron homeostasis (“network Mendelian randomisation tools”)38 b) assess the “de-confounding” ability of these tools by examining their associations with a wide range of traits and phenotypes (“phenome scans”). We will access broad phenotypic information in INTERVAL (>500 phenotypes), in other extensively-phenotyped in-house studies (eg, EPIC-CVD [>1000 phenotypes], PROMIS [>500 phenotypes]) and in external studies (eg, UK Biobank) 39-41 c) conduct integrative analyses to test for causality. To provide instrumental variable analyses, we will exploit the availability in INTERVAL of concomitant participant-level information on the “Mendelian randomisation triad”, ie, genotypes, iron-related biomarkers, and the specific health outcomes listed in WP 2.1 above


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE
Title: Early adulthood education/employment transitions and the development of inequalities in diet quality and cardiovascular health
Funder: Medical Research Council

Abstract: Poor quality diet is one of the key contributors to cardiovascular disease, responsible for 26% of all deaths in the UK. Early adulthood is the age when obesity prevalence increases the fastest and is an important period for development of cardiovascular risk factors. This research project aims to understand how the transitionary period of early adulthood (age 16-24) contributes to development of inequalities in diet quality and cardiovascular health. My research will address the following research questions: 1. How do the socioeconomic trajectories of early adulthood contribute to adult diet and cardiovascular health? 2. How are the education/employment transitions of early adulthood associated with changes in diet quality and eating behaviours? 3. What are the modifiable determinants of changes in diet quality and eating behaviours across early adulthood education/employment transitions? These questions will be addressed through analysis of associations between education/employment transitions of early adulthood, changes in diet and eating behaviours and adult cardiovascular health. I will use the most appropriate existing UK and international cohorts, and collect and analyse new data on diet and its determinants within this age-range in the UK. Data will be analysed using longitudinal modelling techniques (e.g. latent class analysis, latent growth mixture models, causal mediation models and longitudinal structural equation analysis). New data collection will make use of mobile app-based data collection and sensing methods, appropriate for use in a young adult population. Findings from this research will enhance our understanding of the development of diet, eating behaviours and cardiovascular health in early adulthood, and will contribute to the development of more effective interventions and policies to influence development of healthy behaviours.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE
Title: Remodelling of structure-function relationships underlying cardiac dysfunction in ageing: A multi-scale systems approach
Funder: Medical Research Council

Abstract: The primary goals of my project are to: (1) Quantify ageing-associated remodelling of sub-cellular calcium-handling structures, and the extent to which it underlies cellular pro-arrhythmia and the loss of excitation-contraction-coupling; (2) quantify tissue remodelling at the local (mm) and global (cm) scales, and elucidate how these features interact with cellular remodelling to ultimately determine dysfunction; (3) assess the impacts of these remodelling components on the safety and efficacy of pharmacological modulation. These research goals will be addressed through the development of a joint simulation-experimental approach to compare structure and function between young and aged ventricular myocytes and myocardium. Super-resolution microscopy will be used to reconstruct intracellular structure, pertaining to ion channel distribution and membrane structure; histology, optical mapping and MRI will characterise tissue remodelling, pertaining to myocyte arrangement and electrical coupling, fibrosis, chamber size, wall thickness, myocyte orientation organisation; image-based biophysically detailed computational models of cardiac cells and tissues will be used to relate these structures to emergent function. Novel computational modelling approaches will be developed to enable true simultaneous mechanistic analysis of the interactions of structural remodelling across all of the relevant scales and provide the systems-interaction perspective of global function. The computational models will then be integrated with an in silico pharmacology testing platform to determine the interactions of ageing-associated remodelling with pharmacological intervention. Experimental animals will be randomly assigned to one of three groups: young and two time-points of aged; image-based modelling will be performed directly using reconstructions and in the wider space; all computer model code and structural data will be made freely available open-source.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE
Title: Light sheet microscopy in biomedical imaging
Funder: Wellcome Trust

Abstract: We want to purchase a LaVision Ultramicroscope II, the only commercially available light sheet microscope capable of imaging immunofluorescence or endogenous fluorescence in tissues cleared with novel organic solvent-based techniques, including iDISCO (Cell 2014; 159(4); 896-910) and uDISCO (Nature Methods 2016; 13(10): 859-867). The system uses triple sheet optics to create a focused plane of light from a white laser, used in conjunction with appropriate excitation/emission filters. The sample is imaged with specially protected dipping objectives (2x and 20x), which allow rapid 3-dimensional visualisation of multi-colour fluorescence in tissues exceeding 10mm in each dimension, achieving 1-2 micron resolution in all axes. Imaging is conducted using a high-specification workstation, with a separate workstation requested for processing-intensive offline analyses. In view of the large datasets produced, we have applied for 50 terabytes of server storage capacity, managed by IT staff already running the Wellcome Trust funded Astbury cryo-EM facility. We also request support for a half-time grade 5 technician to train new users in the tissue preparation and imaging approaches required to maximise the potential of this equipment. We will use this technological advance to better understand disease mechanisms, test novel therapeutics, and define the potential of 3-dimensional imaging in clinical diagnostics.

Lay abstract: Visualising the body in microscopic detail has fundamentally changed our understanding of health and disease, and has become a cornerstone of modern medicine. Even today, the diagnosis and management of diseases like cancer relies on information collected by microscopes imaging very thin slices of tissue. However, this does not provide an assessment of disease in its 3-dimensional context, and so may overlook clinically useful information. Recent scientific advances allow large pieces of tissue to be made transparent, allowing us to see inside without cutting the tissue. To maximise the potential of this advance, new kinds of microscopes that can rapidly scan large regions are required. We request funding for a specialised ‘light sheet’ microscope to define how these technological advances can aid our research regarding the causes and diagnosis of disease.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE
Title: ‘Harnessing endogenous mechanisms to promote cardiac regeneration’
Funder: Wellcome Trust

Abstract: Ischaemic heart disease remains a major cause of disability and death world-wide. When a major blood vessel in the heart suddenly becomes blocked, the muscle that it supplies dies and is replaced with scar tissue. This is what happens in a heart attack. The scarred heart no longer pumps blood properly and 40% of patients who develop heart failure die within 5 years. There is currently no treatment to help make new heart muscle after a heart attack. We have identified a protein already present in the body, a single injection of which within a few hours after injury can dramatically improve heart function by limiting damage and promoting repair. We will now engineer this protein molecule to retain only the regenerative properties, whilst eliminating potential unwanted effects. We anticipate the engineered product to be safe, limit the damage after a heart attack and also promote regeneration of heart muscle.

Lay abstract: Ischaemic heart disease remains a major cause of disability and death world-wide. When a major blood vessel in the heart suddenly becomes blocked, the muscle that it supplies dies and is replaced with scar tissue. This is what happens in a heart attack. The scarred heart no longer pumps blood properly and 40% of patients who develop heart failure die within 5 years. There is currently no treatment to help make new heart muscle after a heart attack. We have identified a protein already present in the body, a single injection of which within a few hours after injury can dramatically improve heart function by limiting damage and promoting repair. We will now engineer this protein molecule to retain only the regenerative properties, whilst eliminating potential unwanted effects. We anticipate the engineered product to be safe, limit the damage after a heart attack and also promote regeneration of heart muscle.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE
Title: Automated Non-Invasive Coronary Artery Disease Detection Using Artificial Intelligence (ANICAD).
Funder: Wellcome Trust

Abstract: Coronary artery disease (CAD) is the most common cause of death in the UK. Modern medicalimaging scans, such as cardiac magnetic resonance imaging (CMR), allow an accurate, noninvasiveand radiation-free diagnosis of CAD and the early identification of patients that wouldbenefit from available treatments, before complications such as heart attack and heart failuredevelop.There are not enough doctors in the UK trained to accurately interpret these scans, and thisresults in an underutilisation of CMR, also with significant regional variations. We will bridgethis gap by creating computer programs based on artificial intelligence that, acting as expertdigital doctors, will facilitate the interpretation of the scans and guide the clinical team inthe management of patients with suspected CAD. This technology will enable advancedimaging to be rolled out in any hospital equipped with a suitable magnetic resonance scanner,regardless of the presence on-site of trained doctors.

Lay abstract: Coronary artery disease (CAD) is the most common cause of death in the UK. Modern medical imaging scans, such as cardiac magnetic resonance imaging (CMR), allow an accurate, non-invasive and radiation-free diagnosis of CAD and the early identification of patients that would benefit from available treatments, before complications such as heart attack and heart failure develop. There are not enough doctors in the UK trained to accurately interpret these scans, and this results in an underutilisation of CMR, also with significant regional variations. We will bridge this gap by creating computer programs based on artificial intelligence that, acting as expert digital doctors, will facilitate the interpretation of the scans and guide the clinical team in the management of patients with suspected CAD. This technology will enable advanced imaging to be rolled out in any hospital equipped with a suitable magnetic resonance scanner, regardless of the presence on-site of trained doctors.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE
Title: Left ventricle cardiomyocytes: their emergence, identity and maturation
Funder: Wellcome Trust

Abstract: Heart disease is the leading cause of death in industrialized countries. Myocardial infarction (MI) is the most common cause of heart injury. Thus, safe and long-lasting treatments by which damaged heart muscle can be replaced upon MI are urgently required. To achieve this, it is important that we understand how the heart develops, especially the left ventricle. The human heart is different from other mammalian hearts and, for practical and ethical reasons, little is known about its development. I propose to use mouse and human embryo tissue, human pluripotent stem cells (hPSCs) and bioinformatics to study left ventricle cardiomyocyte specification, determination and differentiation. The project will have two main goals: 1) to perform spatial transcriptomic analyses of mouse and human early heart tubes, with the aim of understanding the molecular trajectory of cardiac progenitors towards left ventricle cardiomyocytes; and 2) to utilize this know-how to forward program hPSCs and cardiac fibroblasts towards left ventricle cardiomyocytes. The project will build on my preliminary data, which has identified genes enriched in the left ventricle of mouse embryo hearts. The end point of this project will be to test the efficacy of the induced left ventricle cardiomyocytes for cell therapy and disease modelling.

Lay abstract: Heart disease is the leading cause of death in industrialized countries. Myocardial infarction (MI), commonly known as heart attack, is the most common cause of heart injury. Upon MI, a dramatic loss of contractile heart muscle cells (cardiomyocytes) occurs, particularly in the left ventricle. This can lead to post-infarction heart failure. Conventional medication to treat MI seeks to preserve function rather than replacing/regenerating lost cardiomyocytes. I propose to use mouse and human embryo heart tissue, human pluripotent stem cells (hPSCs) and bioinformatics to study how left ventricle cardiomyocytes form in the developing embryo. The project will build on my preliminary data, which identified left ventricle-enriched genes in developing mouse hearts. A key objective will be to identify the genes and signalling molecules that promote the formation of left ventricle cardiomyocytes, in the hope that this will allow us to generate left ventricle cardiomyocytes from hPSCs to treat heart attack patients.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE
Title: Artificially intelligent predictive algorithms for serious arrhythmias
Funder: Wellcome Trust

Abstract: Transformative creates artificially intelligent algorithms to predict acute outcomes of chronic diseases. Using advanced AI and statistical analysis, our algorithms detect minute changes in patient physiology and predict the imminent risk of serious arrhythmia. Our initial focus is on ventricular and atrial fibrillation. The former is the leading cause of Sudden Cardiac Arrest while the latter is responsible for stroke among elderly patients. Our ultimate mission is to deploy predictive analytics for a wide range of medical conditions. With Wellcome Trust funding, we aim to optimise the algorithms through data obtained in partnerships with hospitals, expand our team of data scientists to accelerate development, and hire software developers to build accompanying software for the algorithms

Lay abstract: Transformative creates artificially intelligent algorithms to predict acute outcomes of chronic diseases. Using advanced AI and statistical analysis, our algorithms detect minute changes in patient physiology and predict the imminent risk of serious arrhythmia. Our initial focus is on ventricular and atrial fibrillation. The former is the leading cause of Sudden Cardiac Arrest while the latter is responsible for stroke among elderly patients. Our ultimate mission is to deploy predictive analytics for a wide range of medical conditions. With Wellcome Trust funding, we aim to optimise the algorithms through data obtained in partnerships with hospitals, expand our team of data scientists to accelerate development, and hire software developers to build accompanying software for the algorithms. Specifically, we aim to: • - Engage with physicians at hospitals to align specifications with clinical practice. • - Extend the predictive window of our algorithms and incorporate additional inputs. • - At data collection conclusion, prepare and submit a manuscript for publication describing performance based on information from all sites.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE
Title: Functions and Applications of a Novel Pluripotency Signalling Pathway
Funder: Wellcome Trust

Abstract: Pluripotent Embryonic Stem Cells (ESCs) have the capacity to differentiate into all cell types, tissues and organs in the adult body. Thus, pluripotent cells holds enormous promise for regenerative medicine, disease modelling and therapeutic testing. A key challenge is to identify the signals that maintain pluripotency and/or drive differentiation, in order to develop novel chemical approaches by which to harness pluripotency and promote lineage-specific differentiation. Recently, I made the unanticipated discovery that the ERK5 MAP kinase pathway drives the naïve state of pluripotency and restricts cardiomyocyte differentiation, thereby acting as a critical switch in defining pluripotent stem cell fate. ERK5 is a very interesting yet poorly understood kinase, which uniquely encodes a catalytic domain and a putative transcriptional activation domain. I will now exploit this exciting opportunity to decipher the molecular functions of ERK5 in pluripotent cells and explore applications of the ERK5 pathway in pluripotent stem cell technologies. The key aims of this proposal are; 1. To identify and characterise ERK5 kinase substrates in ESCs. 2. To elucidate ERK5 transcriptional functions and mechanisms relevant to pluripotency regulation. 3. To exploit ERK5 as a novel target in directed cardiac differentiation of human pluripotent stem cells.

Lay abstract: Embryonic Stem Cells (ESCs) are pluripotent, a property that allows them to form all cell types, tissues and organs in the adult body. Thus, ESCs hold enormous promise for cell replacement therapy and for understanding diseases. However, in order to maintain ESCs in the laboratory, or form tissues and organs from ESCs, we must understand the molecular signals that instruct ESCs to remain pluripotent, or to form a particular cell type, for example heart tissue. My laboratory recently identified a new molecular signal, controlled by an enzyme called ERK5, which instructs ESCs to remain pluripotent and prevents formation of heart tissue. Therefore, the focus of my research is to decipher the proteins and genes that ERK5 acts on to control ESC pluripotency and heart tissue formation, and use this knowledge to improve laboratory-based approaches to develop heart tissue from ESCs for cell replacement therapy and further research.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE
Title: Dynamic regulation of the heartbeat by myosin filaments
Funder: Wellcome Trust

Abstract: The quest for new therapies to improve the function of the failing heart has been impeded by limited understanding of the regulation of contractility in the healthy heart. I recently discovered a new class of regulatory mechanism in skeletal muscle involving the myosin-containing thick filaments, challenging the established paradigm that was limited to calcium-induced changes in the actin-containing thin filaments. My working hypothesis is that the new thick-filament mechanisms mediate the fast autoregulatory responses of the heart, for example the increased ejection of blood in the heartbeat following increased venous return. Although essential to the function of the healthy heart and frequently impaired in heart disease, the mechanisms underlying fast autoregulation in the heart are unknown. Our pilot experiments show that for the first time it is feasible to elucidate these mechanisms by measuring the regulatory states of both the thick and thin filaments on the millisecond timescale in working heart muscle cells in which the normal cardiac cycle is reproduced by dynamic control of muscle cell length, load and intracellular calcium concentration. The results should be transformative for understanding the regulation of contractility in the healthy heart and for the development and testing of new therapies for heart disease.

Lay abstract: Contraction of heart muscle, like that of limb muscles, is driven by sliding between two sets of protein filaments called thick and thin filaments. Contraction of both types of muscle was thought for many years to be controlled by structural changes in the thin filaments. However we recently discovered that the strength and speed of contraction in limb muscles is in fact controlled by structural changes in the thick filaments. We will now investigate how this new thick-filament control system works in the heart, to find out how it adjusts the strength and speed of the heartbeat in response to the varying needs of the body. Understanding the control of the heartbeat at the level of the protein filaments will help to design, develop and test new drugs to improve the function of the failing heart, and the quality of life of those suffering from heart disease.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE