NIHRDataInsights/HRCSData huggingface dataset:
Title: A systems approach to the classification of genes impacting the cardiovascular phenome
Funder: Medical Research Council

Abstract: Genome-wide association studies have transformed the world of genetic association studies, robustly identifying hundreds of loci involved in a wide range of common, complex diseases and traits. This approach tests each genetic variant against a single trait or disease. However, the typically small effect size (per genetic variant) on traits means that the importance of a particular gene in disease may be underestimated or overlooked due to an absence of genetic variants of major effect on the function of that gene (GWAS results only reflect function that is altered by genetic variation). We propose an alternative approach that uses the pattern of effect across several relevant phenotypes (a phenotypic profile or fingerprint ), rather than the magnitude of effect for a single phenotype, to classify which genes in the genome are functionally involved in a particular trait. By training a supervised learning classifier with phenotypic effect vectors from genes of known relevance we aim to be able to classify all other genes, thus identifying new causal pathways and potential drug targets. This systems approach of utilising multiple related phenotypes (eg the coagulation cascade) will provide new insights into genetic pathways and interactions not accessible within single SNP/single trait analyses. The expected outcomes will be novel, generalisable approaches to the identification of disease genes and classification of new genes involved in cardiovascular disease risk.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Developmental Clinical Studies: Inhibition of C-reactive protein for treatment of cardiovascular & inflammatory diseases
Funder: Medical Research Council

Abstract: We propose to develop the C-reactive protein (CRP) inhibitor drug, bis(phosphocholine)-octane (1,8-bis[{[(trimethylammonium)ethoxy]phosphinyl}-oxy]octane), BPC8, to enable a first phase IIa proof of concept study in patients with acute myocardial infarction treated by primary percutaneous coronary intervention. BPC8 is an optimised version of bis(phosphocholine) hexane (BPC6), the first CRP inhibitor drug. We designed this new small molecule chemical entity and showed that it is well tolerated and efficacious in animals. CRP is the classical human acute phase protein, the circulating concentration of which rises from normal values of 1 mg/l to as much as 500 mg/l in the major acute phase responses associated with most serious infections, inflammatory and tissue damaging disorders. CRP binds to ligands exposed on damaged and dead cells, and then activates complement. The powerful chemotactic, opsonic, cytolytic, pro inflammatory and tissue damaging effects of complement kill cells which would otherwise have survived the primary pathology. We have demonstrated that human CRP significantly exacerbates ischaemic tissue damage via a complement dependent mechanism in rat models of acute myocardial infarction, cardiac ischaemia reperfusion injury and ischaemic stroke. BPC6 completely abrogates this pathogenic effect of human CRP and BPC8 will be even more potent. Compelling observational and epidemiological evidence is consistent with a pathogenic role of CRP after human acute myocardial infarction and high acute phase CRP concentrations are also likely to contribute to tissue damage in a wide variety of other traumatic, inflammatory, infective and neoplastic conditions. Targeting human CRP is therefore a valid therapeutic strategy and our patents covering CRP as a target for phosphocholine drugs and our novel bis(phosphocholine) alkane compounds themselves have been granted or are in condition for allowance. Our work on CRP has received continuous MRC Programme Grant funding since 1975 enabling our many contributions, including establishing the universal use of CRP as a clinical analyte, producing the WHO International Reference Standard for CRP Immunoassay (84/506), and solving the 3D structure of CRP alone and in combination with small molecule ligands. Combined with our comprehensive expertise in CRP, the development programme will be managed by Dr Chris Swain, Cambridge MedChem Consulting, who during his long career at Merck led pre-clinical development of the novel NK1 antagonist drug, Emend, through to commercialisation. Supporting consultancy throughout the CMC, pre clinical, regulatory and clinical programmes will be provided by the firm of Advocates Ltd.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Strategic development of stem cell-based therapies for vascular disease
Funder: Medical Research Council

Abstract: Whilst stem cell research has great potential for translation into patient benefits, cell-based therapies are currently limited by lack of knowledge about human stem cell differentiation and about the extent and kinetics of integration and survival of transplanted tissues. Nonetheless, progeny obtained by in vitro differentiation of pluripotent stem cells can provide unprecedented cellular systems for understanding fundamental cardiovascular disease mechanisms, and for drug discovery and testing. Moreover, studies of endogenous tissue stem cells can provide key insights into their role in cardiovascular disease. We are establishing the Cambridge Cardiovascular Consortium to explore the interface between stem cells and cardiovascular medicine. The Consortium will focus on vascular disease, initially using pulmonary arterial hypertension (PAH) as a model, because its genetic basis is known, well-defined patient populations are available, and its molecular aetiology is highly relevant to other common vascular diseases, especially atherogenesis and vessel calcification. The strategic development of the Consortium will contribute great insight not only to PAH but also to vascular disease more broadly, and in future its infrastructure will serve studies of other cardiac and vascular diseases.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CARDIOVASCULAR
Title: Does nitrite reduce ischaemia-reperfusion injury in patients with acute ST segment elevation myocardial infarction?
Funder: Medical Research Council

Abstract: The anion nitrite is reduced to nitric oxide under hypoxic and/or acidotic conditions, resulting in targeted delivery of nitric oxide to hypoxic tissues. Recent work in animal models has shown that nitrite administration at doses well below those which have any effect on blood pressure potently protects against ischaemia- reperfusion injury when administered either before ischaemia or immediately before reperfusion. This proposal will evaluate whether nitrite administration protects against ischaemia-reperfusion injury and reduces infarct size in patients presenting with acute ST segment elevation myocardial infarction.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: A novel role for the plasma membrane calcium pump (PMCA1) in cardiomyopathy and blood pressure control
Funder: Medical Research Council

Abstract: Heart failure (HF) currently affects around 1 million people in the UK leading to an annual financial burden on the health services of over #1 billion, and its incidence is rising rapidly. HF has a dismal prognosis, with patients dying from progressive pump failure or ventricular arrhythmias. Hypertension, which affects around 15% of the general population, is strongly associated with heart failure with 80% of HF patients having hypertension. PMCA1 is a member of a family of four transmembrane calcium transporters that eject calcium from the cell, but whose exact (patho)physiological function remains unknown. We have made the unexpected finding that PMCA1 is involved in all of the central features of heart failure: cardiomyopathy, arrhythmias and hypertension: ? Our cardiomyocyte-specific PMCA1 knockout mice(PMCA1cko) develop severe cardiomyopathy with HF and lethal rhythm disorders. Rhythm disorders occur before ventricular dilatation suggesting a highly specific mechanism. ? Our heterozygote global PMCA1 knockout mice(PMCA1Ht) have raised blood pressure (homozygotes are not viable). ? Three recent genome wide association studies (White, Korean and Japanese populations) by others have identified single nucleotide polymorphisms in the PMCA1 gene as the single strongest association with blood pressure variance in humans. It is the purpose of the present programme to determine the mechanisms underlying the role of PMCA1 in heart failure and high blood pressure at the whole animal, organ as well as at the cellular/molecular level. To this end, we will use our tissue-specific (cardiomyocyte, vascular smooth muscle) PMCA1 knockout mice as well as state-of-the-art in vivo haemodynamic, electrophysiological, functional and molecular techniques. We have 20 years of experience with the molecular biology and (patho)physiology of the plasma membrane calcium pumps; all requisite techniques are long established in our group and we are leaders in the field. This leadership has been recognised and facilitated by MRC International Appointee and programme grant funding since 2001, which has been on PMCA4, an independent isoform of the calcium pump with entirely different functions. This programme is at the heart of the research priorities of the MRC. Firstly, research into heart failure, ventricular arrhythmias and hypertension have been key areas of MRC funding over many years. Secondly, understanding the function of the genes underlying the genetic components of disease (physiological genomics) has been defined as a focus of the MRC (Theme 2, ?Living a long and healthy life?, ?Genetics and Disease?).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Urinary metabolic phenotyping of diet-cardiovascular disease risk associations: the OmniHeart feeding trial
Funder: Medical Research Council

Abstract: Cardiovascular diseases (CVD) contribute to half of the total chronic disease deaths worldwide. The global burden of CVD remains high despite established prevention/control measures for cardiovascular risk factors, such as evidence-based dietary (e.g. DASH diet) and pharmacologic recommendations for adverse blood pressure (BP) treatment. Urgent efforts are needed to advance understanding of the dietary components/metabolic pathways that underly the beneficial effects on BP, and serum lipids of DASH-type diets (i.e. diets rich in complex carbohydrates from fruit/vegetables, grain/legumes, nuts/seeds, reduced in sugar, saturated fat, total fat, cholesterol and sodium intake). This proposal aims to improve understanding of diet-disease risk associations via metabolic phenotyping of the stored urine specimens from a controlled feeding study with a randomised, 3-period crossover design comparing three interventions based on the DASH diet, each intervention with varying amounts of carbohydrate, protein or unsaturated fat, the OmniHeart Trial (N=159). Identification of diet-related urinary phenotypes from OmniHeart and urinary biomarkers for BP/other CVD risk factors will be achieved by integration of the dietary data from OmniHeart with the 1H-NMR analysed urinary metabolite data using multivariate data analysis techniques. In addition, inter-individual differences in metabolic phenotypes and responses to the three dietary interventions are to be explored, in an effort to detect factors potentially explaining inter-individual differences in CVD risk factor responses to the dietary interventions. Targeted biochemical characterisation and quantitation of candidate urinary biomarkers are to be undertaken, and associations of biomarker excretion and BP levels are to be assessed to advance our understanding of the aetiopathogenesis of adverse BP. The proposed study have unique potential to yield new insights into metabolic pathways underlying diet-CVD risk factor associations at the population and individual level. Its results may identify potential therapeutic targets that may inform future public health policy.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Study of Child-Parent Screening for Familial Hypercholesterolaemia
Funder: Medical Research Council

Abstract: A common cause of ischaemic cardiovascular disease in young adult life is the autosomal dominant inherited disorder Familial Hypercholesterolaemia (FH). There are about 100,000 undiagnosed people with FH in the UK population. Identifying affected individuals before the onset of disease is important because statin therapy, which lowers blood cholesterol levels, substantially reduces the risk of heart disease and stroke. A recent meta-analysis of observational studies has shown that a cholesterol measurement in children aged 1 to 9 identified about 90% of affected individuals with only about one per thousand unaffecteds falsely classified as positive. Screening newborns or adults was much less effective. The acceptability of screening children when they attend for routine immunization at 1 to 2 years of age has been demonstrated in a General Practice feasibility study. Each affected child will have one affected parent, identifiable as the one with the higher cholesterol, so screening children provides a means of identifying and treating both child and parent in a systematic manner. This has been called child-parent screening. There is now a need to test the predicted accuracy of child-parent screening in practice with a view to specifying an effective primary care based population screening policy. We propose a study of child-parent screening in 76 UK General Practices, administered through the MRC General Practice Research Framework using DNA analysis on all the children screened (10,000) as the confirmatory test. The results of the study will determine the screen positive rate based on total cholesterol, the detection rate and false positive rate based on DNA analysis and the cost-effectiveness and acceptability of a national screening programme in Britain. This will provide independent scientific evidence on the accuracy of child-parent screening and determine what modifications, if any, to the screening protocol are needed. The study will last three years and cost approximately #833,000.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CARDIOVASCULAR
Title: Reducing socioeconomic disparities in health in later life and promoting healthy ageing: the role of potentially modifia
Funder: Medical Research Council

Abstract: The influence of socioeconomic factors on health persists in older age in the UK; these factors could operate at neighbourhood and individual level. The contributions of neighbourhood socioeconomic factors are likely to be particularly important in later life (>60 years), when individuals are more exposed to their residential context than in middle-age. However, there is little evidence from longitudinal studies on the influence of neighbourhood factors on health in later life. This proposal aims to examine the impact of neighbourhood socioeconomic conditions longitudinally on health in older people in Britain, and to identify pathways underlying these associations. Health outcomes include cardiovascular disease (CVD) and related chronic health outcomes (type 2 diabetes, disability and poor oral health). CVD is a leading cause of morbidity and mortality in older age; examining disability and oral health broadens the scope of studying important health outcomes that determine ‘healthy ageing‘. The objectives are (i) to investigate the influence of specific neighbourhood factors such as economic (income, employment), physical (living environment) and social characteristics (crime, social support) on these chronic health outcomes, and (ii) to determine possible pathways underlying these associations including lifestyle (smoking, physical activity, diet, obesity), novel biological factors (inflammatory markers), treatment provision and air pollution. Whether neighbourhood socioeconomic measures can improve cardiovascular risk prediction in later life will also be examined. The proposed research will be assessed in two longitudinal population-based studies of older British subjects: British Regional Heart Study (BRHS), and the English Longitudinal Study of Ageing (ELSA). These data sources have complementary strengths: BRHS has especially detailed information on health outcomes, lifestyle and biological factors in a cohort of older men followed-up from middle-age; and ELSA includes both older men and women with detailed data on individual socioeconomic factors in later life. Ten-year follow-up data on BRHS subjects aged 60-79 years will be used and 8-10 years follow-up data on ELSA subjects aged 60 years. Data on neighbourhood factors will include the Index for Multiple Deprivation (overall and individual domains) and other characteristics such as living environment from routine national data sources including the Office for National Statistics; multilevel modelling will be used for the analyses. The purpose of the proposed project is - to identify potentially modifiable factors associated with neighbourhoods to improve the scope of preventing CVD and related chronic health outcomes in later life, thereby contributing to healthy ageing; and to reduce social disparities in health in later life.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: CARDIOVASCULAR
Title: Cardiac electrical function, Ca2+ sensitivity and arrhythmogenesis in mice with genetic modifications of Pak1
Funder: Medical Research Council

Abstract: Cardiac electrical function is highly regulated on a beat to beat basis by multiple extra- and intra-cellular signalling pathways through control of the activity of the ion channels across the membrane of the heart cells. How such regulation is designed to maintain normal cardiac function under broad physiological conditions and how it comes into play in the face of disease conditions are important issues to be addressed. Our recent studies indicate a novel role of P21 activated kinase-1 (Pak1) in regulating cardiac electrical and contractile functions. The proposed project thereby aims to further clarify the mechanisms underlying the critical roles of Pak1 in regulating cardiac electrical function, myofilament Ca2+ sensitivity and ventricular arrhythmogenesis using mice with genetic modifications of Pak1. The physiological consequences of targeted modifications will then be investigated at the cellular, tissue, whole heart and organism levels. Multi-disciplinary approaches including in vivo physiology, mechanics, electrophysiology and molecular biology will be used. The work will shed light on a major area of uncertainty in cardiac regulation and directly lead to new therapeutic strategies directed at human cardiac arrhythmic disease.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: The role of Nrf2 (nuclear factor erythroid 2 related factor 2) in the cardiac response to chronic overload stress.
Funder: Medical Research Council

Abstract: Background: Patients with chronic heart failure have substantial morbidity and mortality and new therapies for the condition are required. An imbalance between the production of reactive oxygen species (ROS) and antioxidant defences - known as oxidative stress - is known to be involved in the pathophysiology of heart failure. Recent studies indicate that ROS may regulate both detrimental pathways and protective pathways (e.g. angiogenesis) involved in the cardiac response to chronic stress. The balance between these pathways determines whether the heart adapts to stress or fails. Preliminary studies in genetic models with enhanced protection against chronic stress suggest that ROS-dependent activation of the transcription factor Nrf2 may be an important component of adaptive pathways activated by chronic overload. Nrf2 coordinates the expression of a large number of antioxidant and other cytoprotective proteins and is critical in regulating redox homoeostasis. It is known to be important in cytoprotection in many tissues during cellular stress but its possible role in the heart remains poorly studied. Hypothesis: The activation of Nrf2 and Nrf2-activated genes is a key adaptive mechanism in the cardiac response to chronic overload stress. Aims of project: (1) To establish the role of cardiomyocyte Nrf2 in the cardiac response to chronic overload stress; (2) To investigate the mechanisms involved in Nrf2-dependent protection against cardiac stress. Project objectives, design and methodology: Studies will be undertaken in novel genetic models in which Nrf2 has been specifically deleted in cardiomyocytes. Chronic overload stress will be imposed in Nrf2 knockout and control models by transverse aortic constriction and the cardiac response studied during the development of cardiac hypertrophy and failure. Analyses will be undertaken of cardiac remodelling, ROS production, antioxidant and cytoprotective genes, redox homeostasis and key signalling pathways involved in remodelling - using echocardiography, histology, RT-PCR, immunoblotting and biochemical assays. To study putative mechanisms involved in Nrf2-dependent protection, the following will be studied: myocardial apoptosis, angiogenesis, inflammation, and mitochondrial biogenesis. To assess the interactions among different Nrf2-regulated pathways and processes, a combined transcriptomic/proteomic/metabolomic analysis will also be undertaken. Scientific and medical value: The project will establish the role of Nrf2 in the cardiac response to chronic stress and provide novel data on Nrf2-regulated pathways in the heart. It may lead to the identification of novel therapeutic targets for the prevention and/or treatment of heart failure.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: CAMMIRA: Correction Advances for Myocardial and MUGA Imaging using Registration Algorithms
Funder: Department of Health (England)

Abstract: Myocardial Perfusion Imaging (MPI) and Multiple Gated Acqusitions (MUGA) are important diagnostic modalities in Nuclear Medicine. Respiratory and patient motion, along with the reliance of processing on operator intervention can reduce the sensitivity and specificity of these tests. The objective of this study is to develop the use of image registration as a single tool for motion correction and automated processing of cardiac images to improve diagnostic accuracy. This will be achieved by developing motion correction algorithms for both types of 3D cardiac imaging using an existing image registration toolkit. The same image registration toolkit will be used to automatically derive useful quantitative information from the image data and improve on existing techniques. The algorithms developed will be validated using simulations, tested on patient data, with the outcomes being measured against clinical information and other imaging. The benefits to the NHS would be improved cardiac imaging with minimal associated cost.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR