NIHRDataInsights/HRCSData huggingface dataset:
Title: Properties and function of TRPC proteins in vascular smooth muscle using transgenic mice
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Canonical transient receptor potential (TRPC) proteins are a family of non-selective Ca2+-permeable cation channels (TRPC1-C7) expressed in a plethora of cell types. TRPCs are activated by stimulation of G-protein-coupled and tyrosine kinase receptors, and form Ca2+ influx pathways involved in many cellular functions. In native vascular smooth muscle cells (VSMCs), TRPCs are likely to be heteromeric structures composed of different TRPC subunits, which contribute to vascular disease by inducing excessive vasoconstriction and migration, growth and proliferation of VSMCs. TRPCs and associated signalling molecules are legitimate drug targets for prevention and treatment of cardiovascular diseases. Studies on TRPCs have generally used anti-sense/small-interfering RNAs and dominant-negative technologies to 'knock-down' TRPCs in cultured VSMCs, and VSMC-derived cell lines. These studies have provided useful information on 'what can happen', but do not indicate 'what does happen' in native conditions - cultured cells and cell-lines have different cellular environments, and also may not express different TRPCs compared to native VSMCs. We address these issues by investigating single TRPC currents in acutely isolated VSMCs from TRPC transgenic mice. These approaches will reveal properties conferred by individual TRPCs in native vascular environments, and changes in TRPCs following knock-out of TRPC subunits. Our hypothesis is that TRPC1/TRPC5 subunits confer distinct properties to TRPCs in native VSMCs; small channel conductance, stimulation by agents that deplete internal Ca2+ stores, dependence on protein kinase C (PKC) and phosphoinositols (PIs) for channel gating. We will compare TRPCs in TRPC1-/- and TRPC5-/- VSMCs as these channels are thought to form functional heteromeric TRPC1/C5 channel structures. Moreover, we intend to study the contribution of TRPC1 and TRPC5 proteins to alpha1-adrenoceptor-induced vasoconstrictions.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR
Title: Role of microRNAs in ageing at the blood-brain barrier: integrated studies in human and mouse models
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The aim of the proposal is to test the hypothesis that age-induced changes in gene expression in cerebral endothelium leading to cerebrovascular dysfunction are mediated, at least partially, by changes in microRNA levels. MicroRNAs (miRs) are endogenous non-coding small RNAs that mediate gene silencing by translation inhibition and/or by mRNA decay of target genes. Evidence suggests a role for miRs in regulating the life span of model organisms but the mechanisms involved in this process are largely unknown. One of the first signs of ageing is the loss of specialized functions by cells. The objective of the work is to elucidate general mechanisms by which miRs may modulate normal ageing in a specialized biological system that is amenable to functional, cellular and molecular investigations, the blood-brain barrier (BBB), across two model organisms with differing life spans, humans and mice. First, we will characterize progressive changes in BBB function in humans and mice during normal ageing. Second, using microarray technology, age-deregulated miRs in the cerebral endothelium and age-associated shifts in the global pattern of target gene expression will be analysed so that changes predicted to be directed by alterations in miR levels at the BBB are identified. Third, specific age-deregulated miRs will be selected using their ability to modulate specialized BBB function and/or known pathways of cellular senescence in vitro. Finally, we will validate actions of specific miRs on putative gene targets and confirm age-induced changes in levels of selected miR/target gene pairs at the BBB. BBB dysfunction is recently emerging as an important factor leading to age-associated loss of homeostasis in the central nervous system and we envisage that age-induced phenotypic changes at the BBB mediated by miRs will be identified that may well be not only specific to cerebrovascular function but also constitute general pathways of ageing across biological systems


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR
Title: Physiology of perivascular drainage of the brain and how it is affected by advancing age
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Most organs in the body possess lymphatics by which proteins drain to lymph nodes for maintenance of immune competence and homoeostasis. The brain has no such traditional lymphatics but tracer studies in experimental animals have shown that interstitial fluid drains from the brain along the cerebrovascular basement membranes (BM) to regional lymph nodes in the neck. The same perivascular lymphatic drainage route is present in human brain as shown by the pattern of deposition of amyloid-beta (Abeta) in cerebral amyloid angiopathy (CAA) in the normal elderly brains. The aims of this project are to: 1] Test the hypothesis that the motive force for perivascular drainage from the brain is derived from pulsations in cerebral arteries. We will directly observe the passage of tracers along BM in cerebral artery walls by Two Photon Microscopy. The effects of reduced vascular pulsations upon the efficiency of perivascular drainage will be observed following administration of beta-blockers. Data from this study are important because ageing cerebral arteries lose their elasticity and the amplitude of pulsations is reduced. Reduction in the motive force for drainage may result in deposition of Abeta in artery walls with age. 2] Define the size of molecules or particles that can pass along the perivascular drainage route. Preliminary studies suggest that particles of 20nm may deposit in BMs and temporarily obstruct the perivascular drainage route. So, nanoparticles 10-20nm will be injected to assess how efficiently they are drain along perivascular pathways. Data derived from the study will help to establish the capacity of the normal perivascular drainage pathway. 3] Test the hypothesis that changes in the morphology of BMs in cerebral artery walls with age reflect changes in their proteomics. The data will be essential for future planning of strategies to facilitate the drainage of solutes, from the ageing brain.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR
Title: Development and application of phenolic-rich oats for the maintenance of cardiovascular health
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The intake of dietary-derived phenolic acids, including ferulic acid, caffeic acid and p-coumaric acid have been shown to improve microvasculature blood flow and large artery function in humans. These beneficial effects have been attributed to their potential to improve endothelial function by increasing NO availability. This proposal is designed to test the hypothesis that phenolic acids found within oat-based diets may promote vascular function via their potential to enhance NO bioavailability to the vascular endothelium, through effects on NADPH oxidase activity and NO production. Initially, we will analyse various oat varieties for their polyphenols profile, selecting low and high containing ones for the clinical work. Acute blood flow changes in response to oat intervention will be assessed by conducting a randomised, controlled, crossover intervention study to assess vascular function in healthy human volunteers: Vascular function will be assessed by flow mediated dilatation (FMD) and laser Doppler imaging (LDI). In order that we can make causal relationships between the phenolics in the oats and vascular outcomes, we will also assess plasma levels of phenolic metabolites by using established analytical methods (HPLC with UV-visible, fluorescent and mass detection). We will also assess the modulation of endothelial NO levels by measurement of the circulating NO pool using gas-phase chemiluminescence and the activity of NAPDPH oxidase (enzymatically and by flow cytometry). Metabolic phenotyping/profiling will be undertaken on urine samples (baseline and 24 h) and blood (3 time points) using 1H nuclear magnetic resonance (NMR) spectroscopy. Lastly, the modulation of NO cell signalling (PI3 kinase/Akt and downstream eNOS levels) will be assessed in cultured endothelial cells exposed to physiological phenolic acid metabolites by Western immunoblotting.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CARDIOVASCULAR
Title: Elucidating the mechanisms underpinning direct reprogramming of endothelial cells for use in regenerative medicine
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Cardiovascular disease is the leading cause of death worldwide and is characterised by endothelial cell (EC) dysfunction. Replacing damaged ECs has been recognised as a potential therapeutic option but identification and availability of appropriate cell types has been a major limitation. Recently, a new paradigm of direct reprogramming strategy; "conversion of one somatic cell type to another through reprogramming" has been devised. We reasoned that, at earlier time points during reprogramming, we could direct the epigenetically activated cells which are induced by the iPS cell factors into lineage specific cell types such as ECs under defined conditions without traversing pluripotency. To this end, we adapted a method to generate partially reprogrammed cells, which did not form tumours in vivo and clearly displayed the potential to differentiate into ECs. However, the efficiency of direct reprogramming is very low and the underlying mechanisms remain unclear. Studying the mechanisms underpinning this process should permit for improvements in reprogramming methods and generate fast and efficient strategies. In this study I will elucidate the mechanisms underpinning direct reprogramming of ECs. In particular, it is hypothesised that the direct reprogramming towards ECs is a two-step approach. Initially, the four reprogramming factors activate EC-Regulatory-Networks, which will respond to specific stimuli such as Vascular Endothelial Growth Factor and Fibroblasts Growth Factor and will allow the induction of EC specific markers. This knowledge will allow us to realise fundamental principles of cell reprogramming and establish homogeneous populations of differentiated cells. Importantly, this work will also establish the potential of reprogrammed ECs to enhance angiogenesis and neovascularisation. Together, these findings may establish the therapeutic potential of reprogrammed ECs which would have transforming consequences for regenerative and personalised medicine.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR
Title: AnThocyanin and polyphenol bioactives for Health Enhancement through Nutritional Advancement (ATHENA)
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Anthocyanins are the highly coloured flavonoids that are responsible for the red to dark purple colours of many fruits and vegetables including strawberries, blueberries, blackcurrants and aubergines. Data from epidemiological studies show that there is an inverse relationship between consumption of anthocyanins and risk of disease, particularly cardiovascular diseases (CVD). However, there is a lack of data from high quality randomised controlled trials which are required to establish if anthocyanin consumption causes reductions in CVD risk. The aim of this project is to undertake a highly controlled dietary intervention to assess whether increased anthocyanin consumption reduces CVD risk. This will be achieved using ‘purple tomatoes’ that express high levels of anthocyanins in the tomato fruit and standard red tomatoes that are replete of anthocyanins. Volunteers will be recruited via the local hospital general surgery department; they will be patients who have been referred to have varicose veins surgically removed. They will be randomised to either the treatment or control group and asked to consume 4 portions of tomato soup per week for about 6 weeks. Before and after the intervention, samples of blood and urine will be collected and various measurements will be made of CVD risk factors such as blood pressure and plasma cholesterol, and of other biomarkers associated with CVD risk. In addition, venous tissue will be collected. Non-targeted transcriptomic analyses will be performed using white blood cell fractions and the venous tissue to identify novel markers of exposure / effect, and to guide research into the underlying mechanisms It is expected that the data from this research will establish whether or not anthocyanins, in the context of a complex food matrix, can cause reductions in CVD risk, and will identify potential mechanisms underlying the observed effects.


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION
Health categories: CARDIOVASCULAR
Title: Beneficial effects of dietary bioative peptides and polyphenols on cardiovascular health in humans (Workpackage 2)
Funder: Biotechnology and Biological Sciences Research Council

Abstract: The main objective of the BACCHUS project is to develop tools and resources that will facilitate the generation of robust and exploitable scientific evidence that can be used to support claims of a cause and effect relationship between consumption of bioactive peptides and polyphenols, and beneficial physiological effects related to cardiovascular health in humans. To achieve this, the BACCHUS consortium has assembled 12 leading Research & Technological centres and 16 SMEs. BACCHUS thus contains SMEs directly involved in developing food products and pursuing health claims, experts in health claims legislation and the EFSA review process, and academic and industry partners who provide high quality food and health research that can underpin health claims Existing SME-developed products that have clear potential for obtaining favourable opinions for health claims have been selected as test cases for study. These have been aligned with a series of work-packages each of which addresses key aspects of the EFSA health claim evaluation process (legislation and dossiers; product/bioactive characterisation; habitual intakes; bioavailability; mechanisms and biomarkers; clinical trials evidence of health benefit) that will deliver tools, processes and high quality original science. Scientific results and best practice guidelines will be made publically available and thus support future claims for industry. The scope and completeness of the existing bioactive database (eBASIS) that includes both compositional and biological effects data will be extended and developed as a sustainable tool with various training materials. All outcomes will be disseminated broadly by direct engagement with SMEs via an existing European SME association, with stakeholders via seminars, newsletters and press releases, as well as through traditional scientific routes (high quality publications, and conference presentations).


Research activity codes: 3.3 NUTRITION AND CHEMOPREVENTION;3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION)
Health categories: CARDIOVASCULAR
Title: Health Service Delivery Research to Improve the Quality of Care for Patients with Heart Failure
Funder: Department of Health (England)

Abstract: Evidence-based care delivery for heart failure patients is a growing challenge to healthcare systems worldwide. In two related and complementary projects, I plan to (i) investigate the degree and determinants of variation in quality of care in England and thereby identify best practices, which could help improve service delivery; (ii) develop and evaluate an integrated and scalable remote monitoring and management system for heart failure patients in the community. The findings from this proposal will provide robust scientific evidence on how to improve the quality of care for heart failure patients.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: CARDIOVASCULAR
Title: Safety Culture and the Landscape of Error in Vascular Surgery
Funder: Department of Health (England)

Abstract: The aim of the research is to provide an evaluation of safety culture, error, and adverse events occurring in vascular surgery, in order to inform future safety improvement mechanisms Through the exploration of a) staff attitudes towards influences on safety, b) patterns of intra-operative error and safety failure, and c) in-depth case analyses of adverse events, a comprehensive understanding of current patient safety issues in vascular surgery will be provided. The collective findings of these studies will be disseminated to vascular and patient safety experts, and to patient representatives, and used to develop and pilot safety improvement mechanisms


Research activity codes: 6.4 SURGERY
Health categories: CARDIOVASCULAR
Title: A randomised study comparing vein integrity and clinical outcomes in open and endoscopic vein harvesting for coronary artery bypass grafting.
Funder: Department of Health (England)

Abstract: Objectives: To compare vein integrity, clinical and patient-reported outcomes in three approaches to vein harvesting for coronary artery bypass graft (CABG) surgery. Design: Randomised controlled trial comparing open vein harvesting (OVH), open tunnel endoscopic vein harvesting (OT-EVH) and closed tunnel endoscopic vein harvesting (CT-EVH). Expected outcome: This novel study will provide definitive data to guide selection of optimal vein harvesting technique, with the potential to change clinical practice globally. Benefits: Optimisation of patient outcomes; increased cost-effectiveness; reduction of variation in practice, ensuring that patients are neither denied a potentially beneficial treatment nor treated with a technique which could be harmful.


Research activity codes: 5.4 SURGERY
Health categories: CARDIOVASCULAR
Title: Vascular injury and repair in premature coronary artery disease: understanding the role of endothelial progenitor cells
Funder: Chief Scientist Office (Scotland)

Abstract: Endothelial denudation is one of the earliest pathophysiological features of coronary artery disease, with recurrent vascular injury responsible for the formation, progression and clinical consequences of atherothrombosis. Integrity of the vascular endothelium depends partly on the extent of injury, but also on the capacity for endothelial regeneration and repair through the recruitment of progenitor cells. We hypothesise that premature coronary artery disease occurs due to deficiencies in the number and function of endothelial progenitor cells. Late outgrowth endothelial cells (EOC) can be isolated from peripheral blood and are thought to derive from a true endothelial progenitor cell, but their origin, phenotype and role in the pathophysiology of coronary artery disease have not been identified. We will determine whether EOCs are derived from the bone marrow or from a vascular niche in patients with sex-mismatched allogeneic bone marrow transplants. In parallel, we will reprogramme EOC to gain a better understanding of endothelial differentiation from pluripotent stem cells and provide a novel strategy to identify the precursors of EOC. Finally, we will compare the number and function of EOC in patients with hereditary (family history in first degree relatives <50 years) premature coronary artery disease and matched control subjects. These studies will identify the origin and phenotype of true endothelial progenitor


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR
Title: Development of Interventions to reduce patient delay with symptoms of Acute Coronary Syndrome: identifying optimal content and mode of delivery
Funder: Chief Scientist Office (Scotland)

Abstract: Acute Coronary Syndrome (ACS) is serious and delay to treatment, in particular patient decision time, is a critical factor in reducing mortality and achieving optimal benefit from current treatment strategies. Previous interventions to reduce patient decision time have been largely unsuccessful. However, most interventions have failed to incorporate relevant psychological theory or to use established behaviour change techniques (BCTs). We propose to develop a theory-based intervention by (i) identifying the content (i.e. BCTs) most likely to be effective, based on existing evidence (Systematic Review) and consensus amongst subject experts (Delphi study) and (ii) identifying the most effective way of delivering that content by comparing two modes of delivery (text only and text+visual) with a control in an intervention modelling experiment, measuring effect on intention to seek help immediately. Such an intervention has the potential to achieve significant reductions in mortality and morbidity for this group.


Research activity codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: CARDIOVASCULAR
Title: Development of a reconstruction algorithm for the attenuation correction of myocardial perfusion scintigraphy acquired using novel gamma camera technology without transmission scanning capabilities
Funder: Department of Health (England)

Abstract: Attenuation correction of myocardial perfusion SPECT studies normally requires a separate transmission scan, which can be impractical in the clinical setting. This project aims to develop novel algorithms to reconstruct these studies, including attenuation correction, without a separate transmission scan. This has particular appeal for new instrument designs. An algorithm which uses measured scatter data to estimate attenuation will be developed. The algorithm will then be extended to data acquired using a region centric technique and with respiratory gating. Use of these algorithms has the potential to reduce artefacts in the reconstructed image compared to reconstruction without attenuation correction.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CARDIOVASCULAR
Title: Investigation of the mechanisms and effects of intracoronary nitrite infusion during acute myocardial infarction
Funder: Department of Health (England)

Abstract: Despite advances in the treatment of heart attacks the complications and death rates from failure of the heart to pump properly after treatment remain high. A heart attack occurs when one or more of the arteries that supply blood to the heart become blocked, causing the heart to be starved of oxygen and nutrients. This results in damage to the heart and so the the heart pumps less well. The main treatment for a heart attack is balloon treatment to open the blocked artery (called primary angioplasty). Whilst re-opening the artery is essential and allows blood to flow to the area of the heart starved of oxygen, this process also causes damage itself (called reperfusion injury) and increases the size of the heart attack further. Currently there are no treatments available that reduce this reperfusion injury. We and others have shown that a substance called sodium nitrite reduces reperfusion injury in experimental models of a heart attack. The aim of the research is to perform a trial to investigate whether during a heart attack, an infusion of sodium nitrite into the damaged artery protects against reperfusion injury and reduces heart attack size in patients.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CARDIOVASCULAR