NIHRDataInsights/HRCSData huggingface dataset:
Title: Long-term vascular health effects of cancer and its treatment
Funder: Wellcome Trust

Abstract: There is increasing concern about the long-term vascular health of the large and growing population of cancer survivors. I recently showed that survivors of most types of cancer have increased risks of one or more cardiovascular diseases, beyond those explained by shared risk factors such as smoking. The key priorities now are to understand (i) the drivers of these increased risks, and thus how and when we can most effectively intervene; and (ii) whether broader vascular-related outcomes, in particular dementia and kidney disease, are also affected. In this fellowship I will address these two priorities by conducting analyses underpinned by cutting-edge statistical and epidemiological methods, and capitalising on rich UK and international e-Health datasets, including game-changing new cancer treatment data. I will investigate in detail the role of anti-cancer treatments (e.g. chemotherapies/radiotherapy) and changes in traditional vascular risk factors (e.g. blood pressure, BMI) in driving late cardiovascular risk. I will then investigate whether, and through what mechanisms, cancer history affects risk of vascular dementia, chronic kidney disease, and pre-clinical cognitive and renal outcomes (uniquely identifiable in the 500,000-strong UK Biobank cohort). Throughout, this research will contribute actionable evidence informing clinical/public health policies to improve the long-term outlook of cancer survivors.

Lay abstract: I recently showed that survivors of most cancers have raised risks of heart/circulatory diseases. The key priorities now are to understand (i) why these risks are increased, so that we can work out how best to reduce and manage risk; and (ii) whether cancer survivors are also at increased risks of other circulation-related diseases. I will address these questions by applying cutting-edge statistical methods to analyse large-scale UK and international data sources, capturing detailed information on prescriptions, diagnoses, hospitalisations, and deaths. I will investigate the role of potentially cardio-toxic anti-cancer treatments, and changes in cardiovascular risk factors (e.g. blood pressure), in determining long-term cardiovascular risks. I will then explore whether, and through what mechanisms, having had cancer previously affects long-term risks of two key circulation-related diseases, kidney disease and dementia. These studies will help inform treatment and monitoring guidelines to improve the outlook of cancer survivors.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;CANCER AND NEOPLASMS
Title: Elucidating the interactome and molecular pharmacology of the VEGFR-3 receptor compared to other VEGFR homodimers and heterodimers in vitro and in vivo.
Funder: Wellcome Trust

Abstract: Vascular endothelial growth factor receptor 3 (VEGFR3) is a transmembrane protein found on the surface of cells that line the lymphatic vessels of the body. Its primary role is regulating the growth of new lymph vessels by interacting with its ligands, vascular endothelial growth factor (VEGF) C and D. Recently, VEGFR3 was reported to function in blood vessel development, particularly in cancer (cancer angiogenesis), supporting tumour growth and metastasis. However, our coverage of VEGFR3 pharmacology and signalling in living cells, is poor. Although typically assembled in homodimers, VEGFR3 can also form heterodimers with a different VEGFR isoform, VEGFR2. Comparative analyses of homodimer versus heterodimer configuration, relating to protein signalling and pharmacology is limited due to the difficulty in defining specific complexes. This project will combine the use of two powerful analytical tools, bioluminescence resonance energy transfer (BRET) and BioID to further understanding of the molecular pharmacology of the VEGFRs including Neuropilin receptors. These complementary approaches will allow the interaction of fluorescently labelled VEGF with VEGFR3 to be characterised in real time in living cells with the VEGFR3 ‘interactome’ to mapped, in vivo. Split tags of BioID and NanoBRET will also be used to define the molecular pharmacology of VEGFR2/3 heterodimers.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CARDIOVASCULAR;CANCER AND NEOPLASMS;GENERIC HEALTH RELEVANCE
Title: Trends in complications, morbidity and cause of death in diabetes patients in England
Funder: Wellcome Trust

Abstract: Diabetes is a leading cause of mortality and morbidity in England, with significant impact upon individual patients, and the NHS. Its significance is expected to increase in coming decades due to population ageing and obesity prevalence. Diabetes is associated with several sequelae including heart disease, stroke, and limb amputations, and more recently several cancers and dementia. Work in the US has identified an aggregate reduction in diabetes complications, particularly in vascular complications, with patients experiencing a more diverse range of complications with a growing proportional impact of non-CVD causes. How incidence of complications and mortality has changed over the past two decades in England is unclear. This research fellowships primary aim is to estimate trends in complications and outcomes in patients with type 2 diabetes in England 1998-2018. I will integrate large national datasets including the CPRD, a UK primary care database, linked to Hospital Episode Statistics, the National Cancer Registration and Analysis Service and death records and. Specifically, this fellowship will: 1. estimate trends in age-specific cause of death in patients with diabetes; 2. estimate trends in age-specific incidence of diabetes-related complications and health service-usage; 3. estimate trends in age-specific cancer incidence, survival and mortality in patients with diabetes.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CARDIOVASCULAR;CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE
Title: A cell atlas of the human outflow tract of the heart
Funder: Medical Research Council

Abstract: Congenital heart disease is a major birth defect, and defects specifically affecting the outflow tract (OFT) of the heart represent a third of all CHD cases. Septation of the OFT during embryogenesis is crucial to establish the double circulation found in mammals, which separates oxygenated from de-oxygenated blood. The use of model systems has substantially advanced our understanding of the cell lineages that contribute to the mature OFT. However, human development remains significantly underexplored at the molecular level. In addition, a clear relationship between cell lineages and the cell types found in the adult OFT is still lacking. Here we will define the different cells that comprise the OFT (repertoire of transcripts and accessible regulatory elements) and establish their developmental origin. We will perform massively parallel single-nucleus RNA sequencing (snRNA-seq) and single cell assay for transposase-accessible chromatin (ATAC-seq) on human OFT tissues, isolated from developing (three time points) and adult hearts. Data analysis will capture the developmental trajectories of OFT cells and their contribution to the mature OFT. Thus, this project will define the different cell types that form the OFT of the heart and the gene regulatory networks that control their differentiation, improving our understanding of the causes of cardiovascular disease and paving the way for efficient cell reprogramming and the generation of specific cell types.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;CONGENITAL DISORDERS
Title: LRG1 and dysfunctional vessel growth
Funder: Wellcome Trust

Abstract: Neovascularisation plays a key role in the pathogenesis of diseases such as cancer and diabetic retinopathy. Neovessels are frequently disorganised, poorly perfused and leaky resulting in hypoxia, oedema and ineffective delivery of therapeutics. Until recently, most therapeutic strategies have focused on the inhibition or ablation of these vessels but recent evidence suggests that re-directing abnormal vessel growth towards normality is clinically beneficial. Vascular normalisation has gained traction as a therapeutic concept, but its application to human disease is severely hampered by our limited understanding of the factors that subvert normal angiogenesis. A fundamental conundrum is that many of the molecular drivers of normal vascular development are also responsible for pathogenic angiogenesis, indicating that in disease there are additional factors corrupting this process. We recently discovered a secreted pro-angiogenic factor, leucine-rich alpha-2-glycoprotein-1 (LRG1), that is up-regulated in pathogenic settings and disrupts vessel growth, and we have shown that inhibition of LRG1 results in vessel normalisation. In this study, we will investigate the mechanisms that drive pathological angiogenesis, and test the hypothesis that LRG1 subverts endothelial-mural cell interactions by interfering with or redirecting key signalling pathways. The work will increase our understanding of pathological angiogenesis and pave the way towards new therapies.

Lay abstract: The uncontrolled growth of abnormal blood vessels is a feature of a number of life-threatening and life-changing conditions including cancer, eye disease, atherosclerosis and arthritis. These defective blood vessels can be very harmful. For example, in these new vessels blood flow is often restricted, leading to a reduction in oxygenation, and they can easily rupture causing bleeding into the surrounding tissue. Although some advances have been made in preventing abnormal vessel growth it may, in some instances, be preferable to promote normal vessel growth. To address this problem, we first need to learn more about what causes vessels in disease to grow abnormally, something that is currently poorly understood. Previously we discovered that a molecule called LRG1 is increased in many diseases and promotes the growth of aberrant dysfunctional vessels. We subsequently found that LRG1 subverts normal vessel growth causing them to grow in a chaotic and damaging manner. Our objective in this study, therefore, is to use various systems that model eye disease and cancer in humans to investigate how LRG1 is induced and how it prevents normal vessels from growing. This work will provide fundamental insight into a critical pathological process that has significant clinical relevance.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;EYE;CANCER AND NEOPLASMS
Title: Pericellular mechanisms of fibrillin microfibril assembly.
Funder: Medical Research Council

Abstract: We will determine how the cell-matrix interface of epithelial and mesenchymal cells directs assembly of fibrillin microfibrils, and thus elastic fibres. The objective is to deliver a step-change in ability to restore elastic tissue function following damage or disease, or degenerative ageing changes. How HS/syndecan-4, FN and alpha5beta1 integrin enable microfibril assembly; - Compare in vitro and cell-driven assembly of fibrillin-1 with/without HS (electron microscopy; biochemically; determine role of syndecan-4 (siRNA, mutagenesis, domain swap with syndecans-1/-2; real-time microscopy to track microfibrils); contribution of fibronectin (mutagenesis; fibronectin fragments); - How similar mechanisms regulate LTBP-1 deposition, and thus TGFbeta bioavailability; - How epithelial cell-cell interactions regulate ECM assembly. How ADAMTS10 supports microfibril assembly; - How ADAMTS10 influences fibrillin-1 assembly and higher-order microfibril organisation (electron microscopy; biochemical/biophysical analyses); - How WMS mutations alter microfibril organisation and function (full-length mutant fibrillin-1; assembly assays; microfibril deposition by cells expressing mutant WMS fibrillin-1 (Talen; fluorescence/ real-time microscopy; light sheet microscopy for quantitative live cell imaging). - How ADAMTS10 stabilises cell-cell junctions (effects on microfibril organisation). Design therapeutic strategies to repair elastic tissues. - Test receptor-activating antibodies and fibronectin/HS/ADAMTS10 products (co-culture tissue equivalents); - Regulate receptor activity (antibodies, siRNAs, ECM products in ECM-containing peptide hydrogels, nano-constructs; with Biomaterials, Manchester). Viral transduction, non-viral cationic liposomes or direct exposure to plasmid DNA; - Elasticity of tissue equivalents (microfibril content; nanoindentation, acoustic microscopy).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;EYE;RESPIRATORY;SKIN
Title: Telomere length measurement in UK Biobank: advancing understanding of biological ageing and age-related diseases
Funder: Biotechnology and Biological Sciences Research Council

Abstract: Mean leucocyte telomere length (LTL) will be measured using a well-established quantitative PCR assay which compares the amplification of a telomere length PCR product (T) against a PCR product (S) of a reference single copy gene to produce a T/S ratio. We have extensively validated the assay and confirmed its reliability. To enable a faster and more cost-effective throughput we have developed a multiplex assay which allows amplification and quantification of both T and S in the same reaction to achieve an average weekly throughput of ~5000 samples per week (ie, completion of LTL assays for 500,000 participants within 3 years). We will characterise any independent cross-sectional associations of LTL with the following characteristics: - personal (age, gender, ethnicity, birth weight) and lifestyle and environmental factors (e.g. diet, smoking, physical activity) available in UK Biobank. - cardio-metabolic traits and risk factors (e.g. blood pressure, body-mass index, diabetes, pulse wave velocity) and soluble biomarkers (e.g. lipids, glycaemia measures, sex hormones, inflammatory factors). We will also characterise any independent prospective associations of LTL with the following characteristics: - novel cardiovascular traits obtained through MRI imaging such as left ventricular mass and function. - incident fatal and nonfatal cardiovascular diseases such as CAD, stroke, heart failure, atrial fibrillation. To evaluate whether inter-individual LTL variation is causally relevant to the cardiovascular traits and diseases mentioned above, we will use the genome-wide SNP data currently being obtained on UK Biobank participants to identify genetic variants associated with LTL and use these as instruments in mendelian randomisation analyses. The LTL measurements together with metadata from the project will be deposited with UK Biobank so that other investigators can access them for their own studies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE
Title: A brief physiotherapist-led behaviour-change intervention to facilitate walking in older people with peripheral arterial disease: A randomised controlled trial
Funder: Dunhill Medical Trust

Abstract: Intermittent Claudication (IC), a disabling ischaemic leg painon walking,occurs in30%of older peoplewith Peripheral Arterial Disease.Walking is aneffective treatment but participation is low. Funded by the Dunhill Medical Trust, our successful preliminary study demonstrated that abrief, physiotherapist-led, behaviour change intervention was feasible and acceptable.Thisphase II,multi-centre, two-arm, 1:1 independently randomised, controlled trial will recruit192 people (≥65 years) with IC. Walking ability (6-Minute Walk Distance), daily activity (Nottingham Extended Activities of Daily Living Scale), Quality of Life(VascuQol-6), and psychological processes (e.g. illness perceptions) will be assessed before and after (0,3and 6 months) our intervention or usual care.Our 3 month intervention comprises 2x60-minute individual face-to-face sessions and 2x20-minute follow-up telephone calls (incorporating behaviour-change techniques (e.g. action planning), pedometer, manual and exercise log, delivered by physiotherapists trained in motivational interviewing. Data will be analysed usingintention-to-treat group comparisons.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE
Title: An evidence synthesis suite to inform a future randomised trial of reducing anticholinergic related harm in older adults
Funder: Dunhill Medical Trust

Abstract: When prescribing medicines, there is always a balance between the intended benefits and potential harms. Older adults often have multiple conditions requiring medication but they are also at greater risk of harm from medication. We are interested in understanding the potential harms associated with certain medications known as the anticholinergics and how these might be reduced. Many commonly prescribed medications are anticholinergics, including medications for irritable bladder, allergies and sickness. Furthermore, medications commonly used for heart and chest problems may have anticholinergic effects. Our team’s existing research has shown that the more anticholinergic medications taken by a person, the greater their risk of heart attack, dementia, falls and death. We believe that by minimising the number of anticholinergic medications a person takes, we can improve their health and wellbeing. A counter argument is that medications are prescribed for a reason and removing them could do more harm than good. The only way to know for sure whether reducing anticholinergic medication is beneficial is to do a study where some people have medications altered or stopped and others do not. To help us design the best possible study, we are looking for support to do some important background research. There have been many recent scientific reports and papers looking at anticholinergic medications. These are available in various scientific journals, books and websites. We want to gather all of the published science about stopping anticholinergic medications and the effect(s) that this might have. This work is more than a ‘literature review’. To ensure that we do not miss important information, we may need to assess thousands of scientific papers. When we find potentially relevant information, we have to assess the quality of the science and then use statistical techniques to combine results into a single summary. Learning from the research that has already happened will ensure that our future study has the greatest chance of success. This work will allow us to answer three important questions: a) What is the best method to assess the potential risks from anticholinergic medication? b) Have any researchers tried to reduce anticholinergic medications and if so what can we learn from them? c) Which factors help (or hinder) changing the way people prescribe anticholinergic medications? The questions are important for telling us how to design a future study but will also provide valuable information to people prescribing anticholinergic medications now.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;7.3 MANAGEMENT AND DECISION MAKING
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE
Title: Modelling within-individual variation in repeated continuous exposures
Funder: Medical Research Council

Abstract: Repeated measures of biological variables are used for diagnosis and prognosis in a wide range of clinical settings, with measures collected at varying intervals, but typically in months or weeks rather than days. Technological advances have facilitated the intensive collection of data over shorter time periods, such as real-time glucose monitoring. In many instances, the within-person variation in the repeated measure may be as predictive of future health as the average or rate of change. Although statistical methods for relating the trajectory of such measures to exposures or health outcomes are well-developed, these usually treat within-individual variation as a nuisance. Statistical methods to relate within-individual variability to outcomes are poorly developed and have not been widely used or evaluated. The proposed research will develop methods for modelling within-individual variation in repeated measures, and relating this variation to distal outcomes. We will derive guidelines for the analysis of within-individual variation for different types of repeated continuous measure (normal, skewed) and different measurement schedules (intense, sparse, regular and irregular). We will extend existing Bayesian and frequentist multilevel methods, and examine their performance, in particular with respect to the number of measures per individual. Methods for estimating other aspects of variability (e.g. range) will be developed and applied. We will also use simulations to examine the conditions under which measurement error and within-individual variation can be disentangled. Data on blood pressure during pregnancy (ALSPAC) and ambulatory blood pressure, as well as other studies available to the co-applicants, and simulated data, will be used to test the generalisibility of our methods and conclusions.


Research activity codes: 2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: CARDIOVASCULAR;GENERIC HEALTH RELEVANCE