NIHRDataInsights/HRCSData huggingface dataset:
Title: Translational Medicine and Therapeutics Programme at the University of Cambridge: 'The apelin-ACE-2 axis in cardiopulmonary disease'.
Funder: Wellcome Trust

Abstract: The objective of the project is to test the hypothesis that apelin signalling is altered in PAH and that apelin may be a new mediator and potential new drug target for this condition. Basic and translational research into the pharmacological actions of apelin has been hampered by a lack of selective agonists and antagonists. Two novel molecules have recently been discovered by the group: MM07 an agonist and MM54, a competitive antagonist at the apelin receptor (APJ). This project will focus on identifying the cellular expression of apelin and APJ and measuring APJ densities and pharmacological characteristics in lung and right ventricle from patients with PAH to determine changes in the apelin/APJ system in this disease. Parallel studies will be carried out in heart and lung of the monocrotaline-treated rat to discover if this model reflects the changes in the apelin system in human tissues. I will determine the effects of MM07 and MM54 on progression of PAH in this animal model to identify whether pathway stimulation or blockade improve outcome. In collaboration with Dr I Wilkinson, I plan to perform forearm plethysmography in healthy subjects. If successful, it would be possible, subject to ethics approval, to perform limited studies in PAH patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Advanced human cardiovascular magnetic resonance spectroscopy.
Funder: Wellcome Trust

Abstract: High-energy phosphorus (31P) containing metabolites (e.g. ATP, ADP and phosphocreatine) are critical to energy flow in the heart. Their occurrence in the heart has been studied by 31P magnetic resonance spectroscopy (31P-MRS) since 1974. One can obtain the spectrum from a localized region of tissue, from which the concentrations of metabolites are calculated and which in turn gives insight into biology. In humans in vivo, technical challenges have hitherto limited the clinical applicability o f 31P-MRS. To realise the longstanding goal of obtaining quality 31P spectra covering all 17 segments of the heart in under 20 minutes, every stage in the protocol must be optimised. Therefore, I propose to address the hardware used for cardiac 31P-MRS, the acquisition pulse sequence, the reconstruction of the acquired data and the post-processing of spectra to estimate metabolite concentrations. In the first instance, I will employ the UK's first cardiac-capable 7T MRI scanner to acquire spe ctra from calibration standards, from skeletal muscle in the leg, and in the heart in order to obtain the enhancement predicted by theory and observed in other organs. The methods created in this work will provide a powerful tool for clinical research such as that led by Prof Neubauer.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Induced pluripotent stem cell models of hereditary cardiomyopathy.
Funder: Wellcome Trust

Abstract: Stem cells can be made from skin by forced expression of genes found in the early embryo. These cells survive outside the body for a long time, and can produce any kind of tissue. Since they are genetically matched to the donor, they can be used to study hereditary disorders. We want to make these stem cells from patients with hereditary heart disease seen in our clinic, and use them to understand a disease called cardiomyopathy. Currently we know the genetic basis for this condition but we d ont know how the changes in the DNA blueprint go on to cause end-organ damage. If we could discover this we may be able to find new treatments. But studying this mechanism in living heart cells is difficult because the things thought to drive the process are intimately linked to contraction. This means they change rapidly and reversibly in a moving cell. We believe that light emitting reporters and advanced microscopy will allow us sufficient resolution in space and time to work out what is goin g wrong. Although we are starting with a rare disease which avoids problems associated with this model this work establishes an approach that will have broad implications.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: The G protein-coupled receptor GPR35 in cardiovascular disease: downstream signalling, functional selectivity and potential as a therapeutic target
Funder: Wellcome Trust

Abstract: G protein-coupled receptors transduce extracellular signals to cytoplasmic G proteins and other adapters. G protein-coupled receptor 35 (GPR35) has been associated with various diseases, including cardiovascular disorders such as hypertension, coronary artery disease and heart failure; however GPR35 is still poorly characterised and its precise role in disease remains unclear. The project will investigate the role of GPR35 in cardiovascular disease by addressing four key goals: Develop tools for the study of GPR35 activation. GPR35 and phospho GPR35 antibodies and G protein and arrestin selective GPR35 mutants will be generated. Determine the pathophysiological effects of GPR35 on the cardiovascular system. In vitro models of various cellular cardiovascular components will be used to assess migration, proliferation and hypertrophy in response to GPR35 modulation. The pathophysiological consequences of GPR35 modulation will be studied in vivo in a rat model of hypertension. Characterise a GPR35 knockout mouse. Blood pressure, vascular resistance andend-organ damage will be assessed in GPR35-deficient mice under basal conditions and following challenge with a range of pathological stimuli. Assess the role of G protein and arrestin dependent signalling pathways. Signalling downstream of GPR35 activation will be studied in cells expressing wild type receptor or G protein and arrestin-selective mutants.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Investigating the role of the bone morphogenetic proteins in the development of atherosclerosis.
Funder: Wellcome Trust

Abstract: Atherosclerosis, a major cause of cardiovascular disease, affects millions of people every year. Atherosclerosis is characterised by vascular inflammation, lipid deposition and calcification in arterial walls. Evidence has shown that bone morphogenetic proteins (BMPs) are involved in thedevelopment of atherosclerosis. For example enhanced BMP2 activity has been implicated in triggering pro-inflammatory effects on the endothelium by accelerating vascular calcification. Although BMPs have been shown to promote atherosclerosis, paradoxically, reduced expression of the bone morphogenetic protein receptor-II (BMPR-II) has been shown to induce inflammation of the endothelium both in vitro and in vivo. The hypothesis underpinning this research project is that BMP signalling is involved in atherosclerosis. However, the mechanisms by which specific BMP ligands and their receptors contribute to or protect from disease, and the cell-specific nature of these responses remain unknown. The key goals of this study are: o To determine the effects of BMP ligands on the interaction between monocytesand endothelial cells. o To characterise BMP signalling in a mouse model of atherosclerosis. o To investigate the cell specific nature of the BMP signalling in atherosclerosis using a conditional knock-in mouse. o To apply the knowledge gained from investigating the aforementioned scientific questions with the view to intervene therapeutically.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: The Role of miR-208 in the Molecular Mechanism of Post-operative Atrial Fibrillation.
Funder: Wellcome Trust

Abstract: Atrial fibrillation (AF) is the most common post-operative complication after heart surgery, affecting approximately 1 in 3 patients. Not only can AF prolong a patients stay in hospital after surgery, but it may precipitate chronic illness, reduce survival and contribute considerably to NHS expenditure. Currently, it is not possible to identify patients at increased risk of AF. MicroRNAs (miR) are small regulators of gene expression that may act as potential biomarkers of disease processes inclu ding heart failure. Our early work has identified miRs present within the heart tissue that have the potential to characterise patients at risk of AF 2-3 days before the condition occurs. My aim is to develop a simple blood test based on my initial results to enable the identification of patients at risk of AF at the time of pre-operative assessment. Further to this, by identifying the underlying mechanism by which these changes occur I aim to identify new treatment targets and enhancing prevent ative strategies in this high risk patient group.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Cardiovascular disease in Russia: strengthening evidence about causes, mechanisms, prevention and treatment.
Funder: Wellcome Trust

Abstract: Russia has very high mortality from heart disease: four times that of the UK. This is one of the main reasons a 20 year old man in Russia today has only 1 chance in 2 of living to retirement if things do not improve. Although much is known about the causes of heart disease, in Russia the disease has many unusual features that differ from the pattern seen elsewhere, and is not explained by known factors such as cholesterol. Building on 20 years of work in Russia, we will carry out the most c omprehensive study of cardiovascular disease there to date. We will analyse patterns and trends in the burden of cardiovascular disease in Russia, and undertake surveys of the cardiovascular health of working-age men and women using state of the art technologies. These will identify any novel features of CVD pathology in Russia and new biological mechanisms underlying them. We will investigate how methods to prevent and treat cardiovascular disease in Russia could be improved and their costs and benefits. Ultimately, we aim to inform policies that will improve the health of the Russian population and identify new risk factors that may have relevance to cardiovascular disease worldwide.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CARDIOVASCULAR
Title: A Global Database on Cardiovascular Risk Factors .
Funder: Wellcome Trust

Abstract: Cardiovascular diseases (CVDs) are the leading global causes of death and disease burden. Population-level research on determinants and health consequences of CVD risk factors is constrained by the absence of comprehensive, consistent, and comparable risk factor data. We propose to develop and make publicly available a research-oriented global database on major cardiovascular risk factors, including body mass index, waist circumference, and waist-to-hip ratio; diastolic and systolic blood pres sure; serum total cholesterol, LDL and HDL cholesterols, and serum triglycerides; fasting plasma glucose, postprandial glucose, Haemoglobin A1c, and diabetes prevalence; and smoking. The resource will include both the original extracted country data and consistently and comparably estimated country trends between 1980 and 2015; it will have a web-based platform for accessing and visualizing the data and the country trends numerically and graphically. The proposed resource will be the definitiv e source of data for population-based research on cardiovascular risk factors. Importantly, the resource's technical development and its management and partnerships are designed to facilitate global sustainability in data quantity and sustainability in data quality, consistency, and comparability. This will be achieved by creating the infrastructure for efficient updates and establishing regional nodes who will regularly update the database after the project's completion.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CARDIOVASCULAR
Title: Investigations on the role of cytoskeletal regulators in angiogenesis
Funder: Wellcome Trust

Abstract: Angiogenesis is the term given to the branching of new blood vessels from existing vasculature; this activity extends, matures and maintains the primaryvascular network formed during early embryogenesis. The resulting circulatory system plays an essential role in physiology and consequentially disruption toits formation and conservation is a contributing factor to a vast number of diseases. As a pre-requisite to the development of treatments for vascular diseases, a large part of scientific research focuses on understanding the mechanisms governing the angiogenic process. Although many questions still remain the importance of the cytoskeleton in blood vessel outgrowth is clear. For this project I will take three cytoskeletal-associated proteins previouslyhighlighted as candidate angiogenic regulators. I will be investigating the role of the GEF Dbs, the fomin Daam2, and the GAP srGAP2 in endothelial cells.Using a mixture of in vitro and in vivo techniques I wish to determine whetherthey contribute to angiogenesis, and if so what signals do they respond to andwhat are the consequences of their deregulation. It is through these answers that I hope to further characterise the complex network of regulatory signals governing the angiogenic process.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR
Title: Towards a healthier and environmentally sustainable edible oil consumption profile for Asia
Funder: Wellcome Trust

Abstract: Palm oil, a ubiquitous food ingredient, has brought economic benefit to Asia, but has been linked with negative health and environmental outcomes. Previous research has found strong associations between palm oil intake and mortality from cardiovascular disease, and between oil palm production and environmental degradation. Given consumption trends in the region, potential health impacts flowing from careful policy development to restrict intake are substantial. The proposed work will break new ground in terms of (i) investigating health, economic as well as environmental aspects of palm oil, and (ii) integrating health as well as environmental aspects with a whole-economy macroeconomic model. We propose a pilot project for Thailand to (i) examine interconnections between economic, health and environmental dimensions of palm oil production and consumption. (ii) Identify and simulate the impacts of a set of policy-relevant scenarios, and (iii) test methods and data assimilation procedures, preparing the ground for a follow-on regional project. Our modelling approach involves integration of data and combination of Thailand-specific macroeconomic and health/demographic models with an environmental module. Policies will be simulated, and economic, health and environmental impacts estimated. Trade-offs and synergies will be examined, and policy recommendations made.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: CARDIOVASCULAR
Title: Vascular Inflammation Imaging Using Somatostatin Receptor Positron Emission Tomography - The Vision Study.
Funder: Wellcome Trust

Abstract: In many people, over time, fatty deposits (called plaques) build up in the walls of the vessels that carry blood to the heart and brain. This occurs as part of a process called atherosclerosis (hardening of the arteries). In some people, these plaques rupture, causing a blockage in the blood flow to certain parts of the body. This is how heart attacks and strokes occur. Atherosclerosis occurs over many years, and this causes gradual narrowing of vessels. Some people experience symptoms when the narrowing becomes severe, such as chest pain while walking. However, many people do not experience symptoms to warn them that are at risk. Therefore, we want to look for better ways to identify people who are at increased risk so that treatment can be started early. We know that inflamed plaques are more likely to cause problems However, the tests we currently use cannot see inflammation. This study will test a new type of scan that can measure the amount of inflammation in the arteries. If suc cessful, our scan could be used to identify people at risk of heart attacks and strokes, to rapidly and cheaply test new medicines and to help us understand the disease better.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Defining a novel molecular mechanism in VEGF-induced vascular hyperpermeability
Funder: Medical Research Council

Abstract: Stimulating therapeutic blood vessel growth with the angiogenic growth factor VEGF is considered a promising treatment for ischemic diseases that significantly impact on human health. However, VEGF also causes excessive vascular permeability and thereby promotes tissue oedema. The VEGF receptor NRP1 is essential for vessel growth through angiogenesis and arteriogenesis, but has also been implicated in vascular hyperpermeability. We previously generated mice expressing a truncated NRP1 protein that retains only the transmembrane and extracellular domains, but lacks the cytoplasmic domain. We reported that these mice have normal angiogenesis, but reduced ischemic arteriogenesis. Our unpublished observations show that these mice are also defective in VEGF-induced vascular permeability, even though the NRP1 cytoplasmic domain is thought to lack signalling capacity. Our pilot data additionally show that the only known binding partner of the NRP1 cytoplasmic domain is dispensable for VEGF-induced vascular leak, suggesting that NRP1 promotes vascular permeability in a mechanism that remains to be identified. Our pilot data also show that loss of the NRP1 cytoplasmic domain attenuates vessel leak in an experimental model of inflammatory disease without perturbing neoangiogenesis. We will combine the use of primary endothelial cells for cell and biochemical studies and small molecule inhibitor screening with vascular permeability assays in skin, eye and other organs of wild type and mutant mice with defective VEGF and NRP1 signalling to define molecular differences in the NRP1-mediated signalling pathways that distinguish VEGF-induced vascular permeability from VEGF-induced angiogenesis and arteriogenesis. We will also examine if perturbing VEGF-induced permeability impacts on leukocyte extravasation. These experiments will establish whether the NRP1 cytoplasmic domain is a novel therapeutic target for the treatment of tissue oedema and inflammation in ischemic disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;BLOOD;STROKE
Title: Radiotherapy-Related Adverse Cardiac Events In Lung Cancer
Funder: Wellcome Trust

Abstract: The most important risk factor for lung cancer is smoking, which also causes cardiovascular disease. Due to other medical problems preventing surgery, or patient preference, many patients with lung cancer receive radiotherapy. Radiotherapy is high-dose X-rays and there are risks associated with this treatment, in particular to the heart. Little is known about why some patients’ hearts appear more sensitive than others. The purpose of the RACING research project is to discover how radiotherapy affects the heart and if radiotherapy heart damage can be predicted before treatment. Laboratory experiments will test how radiotherapy can affect the pump action of the heart, and which parts of the heart are most likely to malfunction, and the mechanism of damage. Patients who’ve had radiotherapy previously will have their CT scans examined by advanced computer software to find clues that could help doctors avoid/reduce radiotherapy heart damage in future patients.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR;CANCER AND NEOPLASMS
Title: Zeb1 signalling in Endothelial Cell heterogeneity
Funder: Wellcome Trust

Abstract: Angiogenesis is the growth of new blood vessels from pre-exisiting vessels. Tumours require angiogenesis to occur in order to access nutrients and oxygen, but angiogenic vessels also provide a route for tumour cells to escape and migrate to distant sites within the body. Endothelial Cells (ECs) line all blood vessels. When ECs are activated by tumour growth they begin to divide and migrate, leading to angiogenesis. ECs exist in various sub-types (i.e. active and inactive) and respond in different ways to stimulation. Transcription Factors (TFs) are proteins that turn genes on/off and are a contributing factor to the existence of EC sub-types. There is evidence to suggest that one TF, Zeb1, is present in inactive ECs and that removing Zeb1 from mice spontaneously causes angiogenesis. This leads us to the hypothesis that Zeb1 plays a role in controlling EC sub-types and leads to activated ECs. To investigate this, we will compare mice with Zeb1 and mice without Zeb1 and examine the effects on individual ECs, exploring how the EC sub-types change. This work will lead to an understanding of how Zeb1 leads to spontaneous angiogenesis and may highlight potential targets for new therapies to tackle tumour angiogenesis in cancer treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;CANCER AND NEOPLASMS