NIHRDataInsights/HRCSData huggingface dataset:
Title: Genetics and genomics of central obesity.
Funder: Wellcome Trust

Abstract: Obesity is a result of an inherited tendency for weight gain acting together with environmental factors (overeating in combination with lack of exercise). Genetic factors can affect appetite, the rate at which individuals burn energy (metabolic rate) and how and where the body stores fat. It is not just the overall amount of fat that matters but where it is deposited. Fat in the abdomen is associated with far more serious effects than fat deposited elsewhere. My hypothesis is that there are dist inct pathways influencing development of overall obesity and central obesity, with the latter involving mechanisms both in brain and fat. Therefore it is not just important to understand the ways in which individuals differ in the total amount of fat that they accumulate, but also to understand differences between individuals in the sites at which fat is deposited. Also, I will try to test possible explanations for how the biological mechanisms highlighted are involved in the control of how fat is distributed over the body. By developing a better understanding of mechanisms regulating central fat storage we may learn what biological pathways we should target for drug intervention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: STROKE;CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE;CARDIOVASCULAR;ORAL AND GASTROINTESTINAL
Title: Centre of excellence in diet and physical activity public health.
Funder: Wellcome Trust

Abstract: The proposed Centre of Excellence at the Institute of Public Health, Cambridge focuses on two main themes of the UKCRC initiative by promoting research excellence in public health research related to diet and physical activity. These two behaviours are strongly linked to the rise in non-communicable diseases such as cancer, lschaemic heart disease stroke and type 2 diabetes which are major contemporary public health problems. Rather than tackle these behaviours separately, the proposed Centre explicitly considers them together. The problem of the rising prevalence of obesity demonstrates the need for this approach as any public health solution solely focused on either diet or activity is unlike be successful. The Centre brings together researchers with an established international track record in diet and physical activity research, epidemiology, biostatistics, health economics, behavioural science, intervention development and evaluation. The Centre builds on the strong foundations of expertise in the measurement and descriptive epidemiology physical activity and dietary behaviour, the study of the links between diet and activity and chronic disease and the development of preventive interventions. As a Centre within an existing institute with multiple MRC Unit contributions, there are clear established links to under-pinning methodological research for public health science. The overall goal of the Centre is to develop effective public health interventions for changing population-level diet and physical activity behaviour. The Centre's work is organised around 4 age-defined research programmes aimed at pre-school children; school aged children and adolescents, working age adults and retirement age adults. Within each programme a range research projects is planned, which make use of a core organisation and research infrastructure. The projects range from early work on understanding the determinants of activity and dietary behaviour, through intervention development to evaluation of effectiveness.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: STROKE;CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE;CARDIOVASCULAR;ORAL AND GASTROINTESTINAL
Title: Analysis of rare variation in population and family studies
Funder: Wellcome Trust

Abstract: Genome wide association studies have been successful in identifying novel locithat contribute to complex human traits. However, the SNPs identified by these GWAS typically explain a small proportion of genetic variation in the population, leading to the problem of missing heritability. Rare variants have been shown to contribute in part to this missing heritability. So far, majority of the methods for analysing rare alleles have been developed for application to population based samples. In this project, we will develop methodology for: (i) assessing the impact of rare variation within functional units on complex quantitative and binary traits in family-based association studies (trios or mother-child pairs); and (ii) combining the results of rare variant analyses from family-based and population-based association studies. We will perform simulations to assess the validity and performance ofthese approaches over a range of complex trait genetic architectures. The methodology developed in this project will then be applied to family- and population-based exome-chip data from PIVUS, ULSAM and the Berlin Birth Cohort, for a range of complex traits including type 2 diabetes, obesity and glycaemic measures


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: STROKE;CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE;CARDIOVASCULAR;ORAL AND GASTROINTESTINAL
Title: Metabolic consequence of in vivo modulation of discrete serotonergic pathways.
Funder: Wellcome Trust

Abstract: Drugs augmenting serotonin bioavailability are among the most clinically effective compounds for weight loss and represent the gold-standard for obesity treatment research. Due to sibutramine's withdrawal from the clinic and the recent failure of the serotonin2C receptor agonist lorcaserin to achieve FDA approval, a major unmet clinical need has emerged. Here we propose a refined strategy to dissociate and manipulate a critical serotonin energy balance pathway in an effort to circumvent off-tar get effects produced by global serotonergic compounds and selective serotonin receptor agonists. Building on work generated in the previous funding period where we characterised a downstream pathway required for serotonin to regulate energy homeostasis, here we propose cutting-edge techniques coupled with recently developed tools to delineate and manipulate in real-time serotonin efferents providing these critical inputs to coordinate energy balance. Furthermore, we will interrogate the effect of dietary choice and adiposity on serotonin neuron sensitivity to these inputs and nutritional signals. Finally, we will delineate nutrients and nutritional cues that directly influence the sertotonin neuron activity, with the aim of revealing new system-specific targets for obesity pharmacotherapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: STROKE;CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE;CARDIOVASCULAR;ORAL AND GASTROINTESTINAL
Title: Molecular and neural basis of obesity
Funder: Wellcome Trust

Abstract: Finding better ways to both prevent and treat obesity has become a major public health concern. Whilst changes in diet and lifestyle have driven the increase in obesity, some people are particularly prone to gain weight more easily than others and these differences between individuals are due to our genes. The aim of my research is to discover the genes involved in controlling weight by looking for defects in such genes in children who are obese. I have shown that defects in genes involved in th e leptin-melanocortin pathway cause obesity. These discoveries have led to the successful treatment of patients with leptin deficiency. I now propose to use the latest technologies to find new genes by studying over 4000 obese patients recruited to the study I have established. I intend to work out how these genes regulate the amount of food we eat, how we burn up calories, and how weight problems influence the risk of diabetes and other complications. In this way, I hope to learn more about why some people gain weight and thus find better ways to both prevent and treat obesity.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: STROKE;CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE;CARDIOVASCULAR;ORAL AND GASTROINTESTINAL
Title: Does methylation mediate the effect of physical activity on obesity in childhood?
Funder: Wellcome Trust

Abstract: Evidence implies that there is an association between physical activity and DNA methylation and between DNA methylation and obesity. I will explore the potential mediating relationship of methylation in the relationship between physical activity and obesity, using epigenome-wide data which have only recently become available on this scale. I will start by performing epigenome-wide association analyses to identify differentially methylated regions at age 7 years and at age 15-17 years associated with variation in physical activity (PA-DMRs). I will assess whether these PA-DMRs are associated with obesity-related traits. I will then longitudinally model how the PA-DMRs that I find change between age 7 and age 15-17 years in relation to physical activity levels across childhood. I will use Mendelian randomisation to investigate causality in any associations that I find. I also plan to investigate the underlying biological mechanisms that the PA-DMRs may be acting through.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: STROKE;CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE;CARDIOVASCULAR;ORAL AND GASTROINTESTINAL
Title: Treatment of obesity with the pancreatic polypeptide analogue PP 1420
Funder: Wellcome Trust

Abstract: Obesity is a massive health problem worldwide. Currently, no medication is effective. We have developed PP 1420, which uses the body's natural satiety system for controlling appetite. It is given as an injection under the skin once a day. It works by suppressing appetite. We have previously tested it in healthy volunteers, and found that it is safe and well tolerated. We wish now to study PP 1420 in a further cohort of healthy volunteers to show that it is able to reduce food intake and body weight, when multiple doses are given.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: STROKE;CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE;CARDIOVASCULAR;ORAL AND GASTROINTESTINAL
Title: Is the cross-talk between innate immune cells, skeletal muscle and adipose tissue altered with ageing, and is this pathological cross-talk exacerbated in elderly obese individuals?
Funder: Wellcome Trust

Abstract: Ageing is associated with a decline in skeletal muscle mass (sarcopenia), increased adiposity and a decline in innate immune function (immunosenescence). Recent studies suggest crosstalk exists between innate immune cells (NK cells), skeletal muscle, and adipose tissue. This cross-talk may mediate sarcopenia and immunosenesence. Immune cells infiltrateageing skeletal muscle; this is enhanced in obese individuals. These immune cells secrete growth factors and cytokines that are known mediators of skeletal muscle remodelling.In turn, sarcopenia and obesity alter the expression of adipokines/myokines (e.g IL-15), which impact on NK cell functionality. Indeed, polymorphisms in IL-15 and IL-15R have been


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: STROKE;CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE;CARDIOVASCULAR;ORAL AND GASTROINTESTINAL
Title: The importance of phosphatidylcholine biosynthesis in adipose tissue macrophages during obesity.
Funder: Wellcome Trust

Abstract: The mechanisms linking adipose tissue macrophage (ATM) inflammatory polarization and systemic inflammation during obesity are not fully understood. ATMs accumulate lipid droplets during obesity, and modulating the capacity of macrophages to store lipids alters their inflammatory properties. Our lab has recently shown that phosphatidylcholine biosynthesis is up-regulated in the ATMs of obese mice. CTP:phosphocholine cytidylyltransferase (Pcyt1a), a rate-limiting enzyme in phosphatidylcholine biosynthesis pathway, is known to be necessary for appropriate lipid droplet formation. We hypothesise that Pcyt1a gene is required for the appropriate ATMresponse to store lipids and may play a role in regulating macrophage polarization. To validate this, we will investigate a macrophage-specific Pcyt1a knockout in diet and leptin deficiency-induced obesity models. We expect that deleting Pcyt1a will render ATMs unable to cope with increased lipid levels, which will result in an increased systemic inflammation. This will be evaluated by characterizing the inflammatory and lipid profiles of


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: STROKE;CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE;CARDIOVASCULAR;ORAL AND GASTROINTESTINAL
Title: Spatial, social and environmental determinants of malnutrition in Africa: a pilot in Kenya
Funder: Wellcome Trust

Abstract: Our vision is to understand the changing nutritional landscape across sub-Saharan Africa in order to develop targeted and effective interventions. We will apply well-established methods developed for infectious diseases such as malaria to understanding and visualising the burden, spatial distribution and determinants of over- and under-nutrition in sub-Saharan Africa. We will create: i) a new understanding of malnutrition, reflecting diverse ecologies and determinants on the continent; ii) maps that clearly characterise the current burden and distribution of malnutrition; iii) predictions of future trends (e.g. with increasing urbanisation, climate change or interventions); and iv) tools to directly guide strategies to improve health, and for advocacy. The pilot phase will be in Kenya. We will combine data from national surveys with remote sensing data, and data from targeted, small area, high-resolution surveys in an urban slum, a coastal rural zone and an arid land zone. The outputs of the pilot will include a continuous national map of nutritional status in children and women, and an understanding of the heterogeneity of prevalence and determinants of malnutrition. Through the pilot, we will identify a set of tools that can be used visualise the nutrition landscape on a continental scale.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: STROKE;CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE;CARDIOVASCULAR;ORAL AND GASTROINTESTINAL
Title: Health and environmental implications of low-carbon, climate-change resilient diets in India
Funder: Wellcome Trust

Abstract: There is currently no information available on the greenhouse gas (GHG) emissions associated with dietary patterns in India, or the possible options for producing low emission, climate-change resilient diets, and their health consequences. This study aims to identify healthy, low-carbon, climate-change resilient diets that are culturally-appropriate and policy-relevant in India. We will characterise dietary patterns in India and estimate their GHG-related emissions. Using mathematical methods these diets will be modified to minimise deviation from current patterns while meeting dietary guidelines for health and minimising GHG emissions and water footprints, incorporating climate-resilient crops where possible. We will provide a suite of policy and climatechange relevant dietary recommendations for the Indian setting. Key goals: 1) Identify current adult dietary patterns and their associated GHG emissions and nutritional content; 2) Characterise the consumers of each pattern with respect to socio-demographics and geography; 3) Identify achievable, culturally acceptable dietary changes for different population groups that will be healthy, low-carbon and climate-change resilient; 4) Quantify the health impacts associated with these dietary changes; 5) Provide a suite of context-relevant options for agricultural, nutritional and health policy makers


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: STROKE;CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE;CARDIOVASCULAR;ORAL AND GASTROINTESTINAL
Title: An ethical analysis of public health obesity campaigns: are such campaigns the proper responsibility of public health bodies, and if so, can they be ethical?.
Funder: Wellcome Trust

Abstract: This research will be focused on producing a timely exploration of the relevant arguments relating to policy and practice arising from public health campaigns about obesity. The aim of my dissertation is to explore the intentions of obesity campaigns, expose potential tensions between the duties of public health and the unintended negative results of these obesity campaigns, and to provide recommendations for the field of public health about the ethical framing of campaigns and health-related me ssaging. Ultimately, I will argue that an ethical public health campaign should be a non-judgmental campaign, meaning that it should not purposefully encourage the stigmatization of a group. Public health agencies can fail to fulfill their duties by presenting potentially-discriminatory simplified messages, which the public interprets as truth and medically sound advice. This project will determine whether a campaign can be both effective and ethical, whether we need an obesity campaign, wheth er an obesity campaign is a government/public health responsibility, and other parameters. It will also bring together some of the most relevant research in public health ethics to provide recommendations for public health policy and practice.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING;8.3 POLICY, ETHICS AND RESEARCH GOVERNANCE
Health categories: STROKE;CANCER AND NEOPLASMS;METABOLIC AND ENDOCRINE;CARDIOVASCULAR;ORAL AND GASTROINTESTINAL
Title: Development of a novel IKACh inhibitor for the treatment of atrial fibrillation
Funder: Innovate UK

Abstract: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia encountered in clinical practice with around 14 million sufferers worldwide. Patients with AF have a 5-fold increased risk for stroke; indeed, in the US approximately 15-25% of all strokes can be directly attributed to AF. The prevalence of AF is predicted to increase by 2- to 3-fold by 2050. Cost of care accounts for ~2.4% of the NHS budget and thus represents a significant burden on healthcare providers. The treatment of AF is, however, controversial and often problematic. Antiarrhythmic drugs are used to convert the atrial arrhythmia back to a normal sinus rhythm and maintain it. However, these drugs are associated with significant and potentially lethal side-effects. There is a substantial unmet need for new safe and effective drug therapies for AF. This programme sets out to develop an orally available drug for the safe and effective treatment of AF; with a substantially improved safety profile compared to current therapies.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: STROKE;CARDIOVASCULAR
Title: Endothelial progenitor cells: potenital biomarkers for diagnosis and prognosis of ischaemic stroke
Funder: Dunhill Medical Trust

Abstract: Endothelial dysfunction represents the early event leading to a host of debilitating vascular conditions including ischaemic stroke. Ageing predisposes the subject to atherothrombotic disease even in the absence of traditional vascular risk factors and is therefore considered amongst the most deleterious elements on endothelium. Thrombolysis represents the standard treatment to restore blood flow to the ischaemic brain. However, due to a short therapeutic window after an ischaemic attack, most patients cannot receive it. Recent studies suggest that bone marrow-derived endothelial progenitor cells (EPCs) may counter endothelial dysfunction and induce neovascularization after cerebral ischaemia. Considering the differences in aetiology and neurological outcome of ischaemic strokes, this study will assess whether variations in the number and functional capacity of EPCs during acute, subacute or chronic phases of disease, as compared to healthy agematched and young volunteers, may be used as markers to predict ischaemic stroke subtype (lacunar or cortical) and patients’ outcome.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: STROKE;CARDIOVASCULAR
Title: The implementation of atrial fibrillation screening in primary care: a mixed-methods process evaluation of the SAFER trial
Funder: Wellcome Trust

Abstract: In atrial fibrillation (AF), the heart beats irregularly. This may produce no symptoms but can cause stroke: 1 in 10 strokes occur in people who do not know that they have AF. Subsequently, there are calls for screening for AF but we first need information on whether screening reduces strokes and is cost-effective. The SAFER trial will study this by comparing the rates of stroke (and other conditions) in general practices that screen to those that do not. Some practices will be given training to perform screening but how they implement it will affect whether screening improves health. I will review evidence for how practices can best implement screening. I will observe how practices implement AF screening by examining training, day-to-day running, consultations, communications, and interviewing staff. I will send quarterly surveys to practices that perform and do not perform screening to see how they differ. I will finally combine my research to discover how best to implement AF screening. My results will guide practitioners and researchers on screening. It will help the trial run AF screening more successfully and explain the trial results more clearly. We can then recommend to screening agencies how AF screening programmes should be run.


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