NIHRDataInsights/HRCSData huggingface dataset:
Title: 11B-HSD1 as a therapeutic target in repair following myocardial infarction
Funder: Wellcome Trust

Abstract: The number of people surviving after a heart attack has increased due to improved early treatment, including use of clot-busting drugs to restore oxygen supply to the heart. However, the heart muscle of survivors is usually damaged and in the longer term this can cause impair the normal pumping action of the heart, leading to potentially disabling chronic heart failure. Using an experimental model of heart attack we have discovered a new pathway that regulates blood supply around the edges of the damaged heart muscle. In the absence of an enzyme called 11 -HSD1, there are more blood vessels and the function of the heart is improved for at least several weeks after heart attack. In the current study we aim to investigate whether it is modification of 11 -HSD1 in heart cells themselves or in non heart-cells e.g. white blood cells, recruited to the heart from the bone marrow to repair the heart, that is important in causing the improvement in outcome. We shall also investigate the abili ty of new drugs that inhibit 11 -HSD1 to increase blood supply and heart function when given after heart attack, and whether loss of 11 -HSD1 activity prevents the development of chronic heart failure.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Clinical PhD Programme at Imperial College London: 'Small-area ischaemic heart disease incidence and survival in England.'
Funder: Wellcome Trust

Abstract: Geographical variations in mortality across England have been documented for almost a century. When broken down by medical causes, one half of the regional differentials in mortality are accounted for by ischaemic heart disease (IHD). It is however unknown what proportion of the variance in IHD mortality among small area units such as wards or local authorities is due to differences in IHD incidence vs. treatment. Incident IHD, unlike incident cancer or sexually transmitted disease, is not comprehensively recorded in England. Thus, while circulatory diseases are the single largest medical cause of death, very little is known about the differences between small areas in incidence or prognosis of IHD. This limits the evaluation of current preventive and health service interventions aimed at reducing IHD incidence and improving survival, especially in the worst-off regions. This project aims to combine three administrative datasets using a Bayesian hierarchical model, in order to develop a consistent and comparable quantification of IHD incidence at small area level in England. The outputs of the project will be estimates of small area IHD incidence and survival. The final part of the project will examine the socioeconomic and health service associations of the variations seen, and will suggest possible interventions to reduce the burden of IHD in aggregate as well as its disparities.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CARDIOVASCULAR
Title: Statistical and computational analyst in cardiovascular disease genetics.
Funder: Wellcome Trust

Abstract: High blood pressure increases risks of stroke and heart attack, which are major causes of death worldwide. Both lifestyle factors (salt and alcohol intake, weight, and exercise) and genetic factors cause high blood pressure. We have already identified some specific genes that affect blood pressure, but their individual effects are small, so there must be many more. Finding these genes and identifying the specific genetic changes responsible leads to better understanding of mechanisms affectin g blood pressure, and may allow us to develop new drugs for lowering blood pressure. New drugs are important because roughly 1 in 3 people taking the currently available drugs do not show sufficient reductions in their blood pressure. We need to identify as many blood pressure genes as possible, because only a small fraction of the genes are viable drug targets. In parallel we are studying the genetic makeup of individuals who already participated in a long term trial of existing drugs for lowering blood pressure and cholesterol. This will allow us to identify why some individuals respond to treatment better than others, and may lead to the development personalised medicine , where a genetic test would help predict which drug or dose is best for each person.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Characterisation of novel long non-coding RNAs in the biology of heart failure.
Funder: Wellcome Trust

Abstract: Initially, it was thought that just 5% of the human genome was transcribed, around one fifth of which can be accounted for by the 20,000 or so known protein-coding genes, or the messenger RNAs (1 ). However mapping and quantification of the mammalian transcriptome has shown that the number of transcripts encoded by the human genome is at least 10 times as great as the number of identified 'genes' (2, 3) that up to 70% of the mammalian genome is transcribed (4). Much of the uncharacterised transcriptors appears to be composed of long non-coding RNAs (lncRNAs), defined as RNA transcripts greater the 200nt (5), 34 of which have so far been associated with human disease (6). To begin the genome-wide search for candidate lncRNAs associated with heart failure, the Foo lab carried out RNA-seq on RNA isolated from four human control hearts and four diseased hearts. Diseased he are from male subjects, aged 40-60 years with a well-documented medical history. RNA-seq is a high throughput sequencing technique in order to obtain information about the biological system's total RNA repertoire (7). The resulting information is a summary statistic- a form of 'read count' that is linearly related to the abundance of the transcript in the sample. Figure 1 shows a diagrammatical outline of a typical RNA-seq experiment. Verify differential expression of transcripts in a larger sample of human heart tissue. Obtain complete sequence of the non-coding transcript. For the RNA-seq derived RNAs, does the transcript reside in myocytes or fibroblasts of cardiac tissue? Ensure that the transcript of interest does not yield a product of translation. What happens when the transcript is overexpressed and repressed in wild type cardiomyocytes or fibroblasts in culture? Is the Inc RNA of interest upregulated in response to stress triggers? What are the interactors of a novel Inc RNA?


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Differential leukocyte counts and the prognosis of specific coronary phenotypes.
Funder: Wellcome Trust

Abstract: People with coronary heart disease (narrowing of the blood vessels supplying the heart) are at risk of developing complications such as a heart attack or death. Doctors try to assess this risk in order to decide how best to treat such patients. Patients routinely have a number of blood tests, including counts of the number of blood cells in the blood. The white blood cells are of particular interest because they may be involved in build-up of material in the walls of the blood vessels, causing t hem to become narrow. Although we know the meaning of very abnormal values on such blood tests, we do not clearly know how 'normal' or mildly abnormal values relate to the risk of future complications. Using large databases of people with heart disease, and a new study following up patients from hospital clinics, we will attempt to better ways of predicting the risk of future complications. We will investigate whether blood cell markers are useful in this regard. We will also investigate well ce rtain medicines work for patients with these conditions. This will help doctors to choose the most appropriate therapies for patients with coronary heart disease.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Dynamic Conduction-Repolarisation Interactions in Ventricular Arrhythmogenesis: The role of the autonomic nervous system & ion channel function in human and murine hearts
Funder: Wellcome Trust

Abstract: Abnormal heart rhythms leading to sudden death claims over 50,000 lives per year in the UK. Fast heart rhythms arising from the main pumping chambers of the heart (ventricular tachycardia, VT or ventricular fibrillation, VF) are the usual culprits. A commonly identified precipitant of these is mental stress, but how this leads to unstable heart rhythms is unknown. Changes in heart muscle activation and relaxation following sudden changes in heart rate (restitution) are critical in the normal re gulation of cardiac rhythms, alterations in these interactions may precipitate VT or VF. We will examine how mental stress and the nervous system affect the electrical activity of patients' hearts. Custom software will be used to analyse changes in the electrical properties of heart muscle simultaneously on the inside and outside surfaces of patients hearts for the first time. We will also perform a parallel study in mouse hearts. By studying mice with known abnormalities in cardiac electr ical activity, we will investigate the mechanisms by which dynamic changes in the activation & recovery of each heart beat occur. This will be an important step in developing novel therapies and preventative strategies for patients at risk of dangerous heart rhythms


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: CARDIOVASCULAR
Title: High resolution 3D late gadolinium enhancement imaging with improved respiratory motion compensation, arrhythmia management and dynamic inversion time
Funder: Wellcome Trust

Abstract: Late gadolinium enhancement (LGE) imaging is a very safe magnetic resonance technique for differentiating between living and dead heart muscle. It is used routinely worldwide to guide treatment decisions for patients with heart disease. However, current 2D breath-hold methods fail to obtain comprehensive coverage of the entire heart and can be problematic and uncomfortable in patients with breathlessness. Attempts at 3D whole-heart acquisitions during free-breathing have been limited by techni cal problems resulting in degraded images that are often not clinically useful. The principal factors accounting for this are motion of the heart (both as it beats and as it moves with respiration) and abnormal heart rhythms during the scanning period. We propose to implement a number of novel solutions for these issues, which will enable reliable high quality LGE imaging during a 5 minute free-breathing period. If funded, this research will have immediate and widespread research and clinical ap plications, such as: (i) improving the accuracy of identifying heart attack patients who are at risk of sudden death and furthering understanding of the underlying responsible mechanisms; (ii) guiding advanced treatments such as arrhythmia ablation and stem cell therapy; and (iii) identifying fibrosis in patients with cardiomyopathy and evaluating new anti-fibrotic treatments.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: DEVELOPMENT OF A NOVEL ARTIFICIAL AORTIC VALVE FOR TRANSCATHETER IMPLANTATION.
Funder: Wellcome Trust

Abstract: Due to the increasing ageing population and consequent change in the main heart valve pathology, a growing group of patients is currently declined from surgical valve replacement because they are judged too ill or weak to withstand the stress of invasive treatments. Transcatheter aortic valve implantation Science 7 (TAVI) represents an ideal answer to the need of this rapidly expanding patients' population, as it allows delivering a valve substitute into the anatomical site through the vascular system, avoiding the need of open heart surgery and its associated risks (e.g. cardiac arrest/restart, extracorporeal circulation etc). Clinical experience with this novel approach has clearly indicated that it is feasible and promising, though it still requires substantial design improvements to enhance the safety and effectiveness of the treatment. The objective of this project is the manufacture and pre-clinical assessment of a novel prosthetic aortic valve suitable for TAVI. Recently designed at UCL, this new valve will overcome the main limitations experienced with the other experimented devices. The proposed valve substitute will be fully retrievable/repositionable, will ensure enhanced anchoring and sealing, will maximise expanded/collapsed diameters ratio and extend durability. Moreover, the functional leaflets will be made of a novel synthetic functional nanocomposite polymer suitable for heart valve applications.


Research activity codes: 5.3 MEDICAL DEVICES
Health categories: CARDIOVASCULAR
Title: Investigating the molecular mechanisms regulating mesothelial cell recruitmentand interaction with forming blood vessels in an in vitro angiogenesis model.
Funder: Wellcome Trust

Abstract: Coronary heart disease (CHD) is the primary cause of death worldwide. Potential novel treatment strategies could involve recruitment of mural cells to sites of ischemia to aid neovascularisation by stabilising collateral vessels surrounding the heart. An important source of mural cells in the heart, lungs and intestine are mesothelial cells (MCs) but details of their recruitment are not fully understood. During development, some MCs undergo epithelial-mesenchymal transition (EMT), regulated by Wilms' tumour gene 1 (Wt1). This process allows MCs to differentiate into vascular smooth muscle cells during recruitment to forming vessels; however the mechanisms of these events are not well characterised. Our preliminary experiments demonstrate that cultured adult MCs, harvested from mouse omentum, successfully align withendothelial tubes in an in vitro angiogenesis assay. Utilising this approach, we will investigate the molecular mechanisms that regulate the recruitment, alignment and attachment of fluorescently labelled adult MCs to endothelial tubes. To mimic the recruitment process in ischemic tissues, we will apply hypoxic conditions. Our study will include an assessment of the role of Wt1 during the recruitment process. Furthermore, we will test the capacity of MCs to contribute to neovascularisation using an in vivo model of CHD.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Transient receptor potential channel 4 (TRPV4): A novel intra-cranial transducer molecule regulating arterial pressure
Funder: Wellcome Trust

Abstract: We are testing the "selfish brain hypothesis" where increases in cerebral vascular resistance trigger neurogenic hypertension, ensuring brain blood flow is maintained. We have shown that increases in cerebral vascular resistance increase sympathetic activity and arterial pressure. The transduction mechanisms by which reductions in brain blood flow trigger hypertension remain unknown. The transient receptor potential channel vanilloid member 4 (TRPV4) is an attractive mechanism. It is a non-selective cation channel that has been implicated in detection of shear stress and the resultant arterial vessel re-modelling. TRPV4 has been shown to be essential in the development of pulmonary hypertension, which involved the novel finding ofTRPV4 as an oxygen sensor. Paton's group have shown that TRPV4 expression exists in the vertebrobasilar circulation and appears essential in the hypertension generated in response to brainstem hypoperfusion. We propose that TRPV4 is an integral part of a novel intra-cranial sensor that equates arterial pressure to maintain cerebral blood flow homeostasis. Since spontaneously hypertensive rats (SHR) have high cerebral vascular resistance and may be hypoperfused particularly during early life when hypertension has not developed, we hypothesise: 1. Vertebrobasilar artery TRPV4 channel expression alters as hypertension develops in the SHR 2. TRPV4 is essential for arterial vessel remodelling that occurs in the SHR 3. TRPV4 allows detection of vertebrobasilar artery hypoperfusion and activates the sympathetic nervous system causing hypertension.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Novel strategies using 'biased'agonists at the apelin receptor for the treatment of cardiovascular disease
Funder: Wellcome Trust

Abstract: Pulmonary arterial hypertension (PAH) is a fatal disease caused by genetic mutations in BMPR-II, or drugs and toxins such as monocrotaline (MCT). We hypothesize this combination of afterload reduction and positive inotropy caused by apelin, the endogenous ligand of the APJ receptor, may be beneficial to PAH. MM07, a synthetic apelin analogue and a biased agonist of APJ, is highly potent in functional assays and less likely to desensitize APJ. Preliminary results indicate that MM07 is stable in vitro and safe in vivo. Our main objective is to study the effects of apelin in animal models of PAH, and in cultured cells. Using the MCT-treated rat meodel, the ability of MM07 to prevent and reverse PAH will be tested. Then the effects of APJ agonism will be confirmed using a competitive antagonist. Additionally, MM07 will be tested in another animal model with a BMPR-II mutation. A non-peptide APJ agonist may also be used to prevent PAH. Furthermore, alteration of the apelin/APJ system will be investigated in vitro in cells from PAH patients. The consequences of these changes and connections with the BMPR-II pathway will be explored. Our findings may support the use of APJ agonists in cardiovascular diseases like PAH.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Characterisation of 18F-NaF as a novel marker for vascular calcification, and development of new treatment strategies for soft tissue mineralisation
Funder: Wellcome Trust

Abstract: Arterial calcification is a process that involves calcium deposition in vessel walls. Mineralization is often found in human atherosclerosis, and a recent report suggests that coronary artery calcium scoring serves as a superior predictor of cardiovascular events. 18F-NaF has been proposed as a reliable marker of vascular calcification. However, it is currently unclear which molecular mechanism are detected using this molecule, which biological processes are involved, and how this informs on plaque rupture risk. To address these issues, we have proposed three aims: Aim 1 is to evaluate the ability of 18F-NaF to quantify calcification in human ex vivo plaque; Aim 2 is to study animal models that can recapitulate the process of calcification using PET imaging for the assessment of calcification and Aim 3 isto examine whether animal models provide a mechanism to test the ability of drugs to alter the calcification process. Together the fulfilment of these aims will allow us to assess 18F-NaF as a novel marker for vascular calicifcation and cardiovascular risk, and test pharmacological treatments with this model. These findings could have important implications to decrease mortality worldwide.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR
Title: Wellcome Trust Clinical PhD Programme at the University of Oxford: 'Approaches to understanding regulatory pathways in atherosclerosis using genome-wide mapping of open chromatin with FAIRE-seq in foam cells.
Funder: Wellcome Trust

Abstract: Approaches to understanding regulatory pathways in atherosclerosis using genome-wide mapping of open chromatin with FAIRE-seq in foam cells. Atherosclerotic vascular disease is the leading cause of morbidity and mortality worldwide. Atherosclerosis is an inflammatory condition and the lesions are packed with immune cells. A key pathogenic role is played by lipid loaded macrophages known as foam cells. The aim of this project is to improve our understanding of the pathophysiology of atherosclerosis to identify new therapeutic approaches. My approach is based on the genome-wide isolation and sequencing of regions of open chromatin in foam cells using FAIRE (formaldehyde-assisted isolation of regulatory elements) seq. Key goals 1. To generate FAIRE-seq data on foam cells, normal macrophages and other control cells. 2. To undertake bioinformatic analysis of this data to identify foam cell-specific regulatory DNA elements. 3. To undertake functional experiments to explore these findings a. At the whole genome level by examining the role of transcription factors or pathways suggested by similarities in foam cell-specific open chromatin regions across the genome. b. At the gene-specific level by examining the function of regulatory DNA elements identified in the MICA gene which encodes an immune ligand which promotes foam cell destruction and further inflammation in atherosclerosis. This project will provide training in a range of techniques involved in immunology, gene regulation, high throughput sequencing and bioinformatics.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Translational Medicine and Therapeutics Programme at the University of Cambridge: 'Mouse models of progenitor and stem cell therapy in BMPRII mutation associated pulmonary arterial hypertension'.
Funder: Wellcome Trust

Abstract: The purpose of this Clinical Lecturers post will be to establish a mouse model of BMPRII dysfunction and derive circulating progenitor cells from BMPRII mutation carriers and wild type mice. This will allow us to test the contribution of differing progenitor cell populations with and without BMPRII mutations, to the processes of vascular repair and new vessel formation, and determine if they have therapeutic effects in a two hit model of disease utilising the R899X heterozygous mouse model in hypoxia and the vascular endothelial growth factor (VEGF) inhibitor SU5416. This pilot data will form the basis of an intermediate fellowship application. The aims of this fellowship will be to determine the frequency, function and kinetics of appearance and loss of ex-vivo expanded vascular progenitors in animal models of PAH. We plan to track and analyse the fate and therapeutic potential of mouse circulating progenitor cell, ESC and iPSC-derived vascular progenitor cells in vivo. Additionally these studies will provide a model for correction of the mutation in BMPRII, and a potential delivery mechanism for introducing repaired cells to the pulmonary circulation.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CARDIOVASCULAR