NIHRDataInsights/HRCSData huggingface dataset:
Title: Treament of diabetic retinopathy by restoring neurovascular health with neuropeptides
Funder: Dunhill Medical Trust

Abstract: While diabetic retinopathy is conventionally classified as a microvascular disease, it is increasingly recognised as a complication of the neurovascular unit, although exact mechanisms remain unclear. We hypothesise that diabetic retinopathy can be prevented or rescued by improvement of neuronal (nerve cells) health through small proteins called neuropeptides. In this project, we will explore the possibility of preventing vascular complications by promoting the health of neurovascular unit through neuropeptides including neuropeptide Y (NPY) and substance P (SP). Through this project, we will be able to answer whether neuropeptides are potential therapeutics and will also enhance the understanding of the mechanisms leading to diabetic retinopathy including the importance of retinal neurons. An added value is through this understanding, development of specialised imaging will aid early diagnosis and determine the right time to treat before damage ensues.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;EYE
Title: Impact of deferring intra-vitreal injections for diabetic macular odemea under the COVID-19 pandemic
Funder: Diabetes UK

Abstract: Impact of deferring intra-vitreal injections for diabetic macular odemea under the COVID-19 pandemic


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: METABOLIC AND ENDOCRINE;EYE
Title: Deep learning for the automated prediction of diabetic retinopathy progression
Funder: Diabetes UK

Abstract: Diabetic retinopathy (DR) affects approximately a third of the 422 million people living with diabetes worldwide, of whom 3.8 million have vision-threatening DR. The number of diabetic people in the UK is reported to be ~4.7 million (6.6% prevalence) and is predicted to rise to >5 million by 2025. We aim to create longitudinal, deep learning (DL) models capable of predicting the risk of DR progression from retinal photographs, and identifying high-risk features associated with DR progression over the subsequent 1 to 3 years. Earlier identification may prompt proactive lifestyle or medical interventions to mitigate the risk of developing vision-threatening DR. By applying model introspection techniques, new high-risk features of DR progression within retinal images may be uncovered, facilitating individualised screening intervals and improving resource utilisation. The proposal builds on impressive results from state-of-the-art, single-time-point DL detection of referable DR (~95% sensitivity/specificity). This research will leverage the UK’s world-leading diabetic eye screening programme, with >2 million patient episodes per year over 10 years, each with retinal imaging. DL models could be used for automated DR progression screening nationally and internationally. Automated DR progression detection could be expanded to optometric and possibly general practices as retinal imaging is fast becoming commonplace.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE;EYE
Title: 2-HDP: a novel therapeutic for diabetic retinopathy?
Funder: Diabetes UK

Abstract: Neuronal and glial cell dysfunction is believed to contribute to the pathogenesis of diabetic retinopathy (DR). Our recent work has shown that accumulation of the acrolein(ACR)-derived advanced lipoxidation end product, FDP-lysine, is a key pathogenic process in the development of neuronal and glial cell abnormalities during DR. Presently, few interventional strategies have been identified capable of preventing the damaging effects of cellular ACR and FDP-lysine accumulation, although the use of direct scavenging agents is considered to be one of the most promising approaches. We have recently undertaken focused, small scale drug screening studies and identified the novel hydrazino compound, 2-HDP, as a highly potent ACR scavenger that is effective not only in blocking retinal FDP-lysine accumulation during experimental diabetes, but also in normalising retinal function (as assessed by ERG recording). In the current proposal, we aim to investigate in greater detail the therapeutic potential of 2-HDP for the prevention of DR. Specifically, we will comprehensively evaluate the ability of 2-HDP to block neuronal and glial cell changes in diabetes and investigate its ability to prevent the vision-threatening complications of this disease. This work could lead to the identification of a new therapeutic option for the early-stage treatment of this condition.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE;EYE
Title: The role of LRG1 in diabetic retinopathy
Funder: Diabetes UK

Abstract: Leucine-rich alpha-2-glycoprotein 1 (LRG1) is a secreted glycoprotein that modulates TGFbeta signaling and in so doing, drives pathological angiogenesis. We have recently obtained data implicating LRG1 in the development of vascular dysfunction in diabetic eye disease. Accordingly, the aim of our proposal is to test the hypothesis that LRG1 expression is induced in the diabetic retina causing disruption to the endothelial cell-pericyte relationship resulting in subsequent vessel destabilisation. We will employ in vitro models to examine the effects of recombinant LRG1 on vascular cell interactions and vessel growth/formation. In mouse studies we will determine the cellular origins of LRG1 in the diabetic retina and use Lrg1 null mutant mice to assess how the early vascular defects observed are moderated in the absence of Lrg1. Finally, we will use diabetic mice to examine the effects of ocular and systemic delivery of Magacizumab, a LRG1-blocking antibody that we have developed and for which we have funding through to early stage clinical trials in wet AMD. The results of this project will provide insight into the molecular mechanisms that drive early retinal vascular disease in diabetes, and provide key experimental evidence to underpin future clinical trials of Magacizumab in diabetes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;EYE;CARDIOVASCULAR
Title: Proteogenomic analyses of tissue-specific networks to study human disease mediated by adipocytes
Funder: Wellcome Trust

Abstract: Fat distribution has been closely linked with a variety of metabolic complications, cardiovascular disease and obesity. Thus, studying genes linked to fat distribution, could lead to important insights that would benefit our understanding of multiple diseases. I am interested in combining genetic studies and proteomic experiments to explore the role of protein-protein interactions in the context of this trait. I will use large-scale genetic studies to nominate genes/proteins involved in fat distribution and subsequently temporally characterize their protein-protein interaction partners throughout fat cell differentiation. Tracking the expression of risk genes and their interaction partners will allow us to build protein-protein interaction networks that represent biological circuits that are functionally important for disease etiology. To understand the consequences of perturbing these networks, I will then use UK-Biobank’s electronic health records to link mutations of individuals within networks to phenotypes. Finally, we will develop a model that incorporates network and individual-level genetic information to predict disease liability. Together, this work will link statistical genetics and proteomic analysis to enable a deeper understanding of the genetic architecture of complex diseases that is driven by fat cell biology.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;GENERIC HEALTH RELEVANCE
Title: A genomics approach to unravelling the link between steroid hormone dysregulation and cardio-metabolic disease
Funder: Wellcome Trust

Abstract: Steroid hormone dysregulation has been linked to nearly all leading causes of death, notably cardio-metabolic diseases. Despite this, the aetiological contribution of steroid hormones to such disease is poorly understood and its potential as a therapeutic target remains largely unexplored. To fill this gap, I seek to pioneer a new aetiological understanding of steroid hormone dysregulation and its health consequences through multiple complementary data-driven approaches. I will do the following: • Identify the genomic basis of steroid regulation through large-scale genetic studies of steroid hormones, steroidogenic enzymes, and regulating peptides. • Pinpoint the tissues, genes and biological mechanisms involved in steroid dysregulation in men and women, through the vertical integration of genetics with tissue-specific molecular trait data. As part of this, I will set up an omics atlas of the adrenal gland and the ovary. • Map out the metabolic and regulatory relationships between steroid hormones and related traits through the identification of genetically determined multi-dimensional steroid traits. • Conduct a genomics-driven identification of new therapeutic pathways and protein targets to correct disease-causing steroid imbalances. In short, this research agenda will not only uncover the aetiological pathways linking the steroid endocrine system to cardio-metabolic disease, but also instigate novel treatment strategies.

Lay abstract: Steroid hormones are chemical messengers influencing multiple processes in the human body, including inflammation, metabolism, sperm production and the menstrual cycle. Steroid hormone imbalances have been linked to nearly all leading causes of death, including heart disease and diabetes. It is unclear, however, if these relationships are causal and what implications for treatment they might have. To fill this gap, I will investigate the biological processes causing steroid hormone dysregulation and how these are linked to the development of cardio-metabolic disease as follows: • I will identify the genetic factors driving steroid hormone imbalances, using large-scale data capturing genetic variation and blood measurements of steroid hormones; • Study how genetic factors influencing steroid hormones affect the biology of specific organs; • Link this information to cardio-metabolic disease outcomes and risk factors. The impact of my research will be to renew our scientific understanding of steroid hormone dysregulation and identify novel targets for treatment.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;GENERIC HEALTH RELEVANCE
Title: Probing cellular heterogeneity in the pancreatic microenvironment
Funder: Wellcome Trust

Abstract: The overarching goal of this proposal is to elucidate the functional diversity of the pancreatic mesenchymal lineage. In embryonic tissues, epithelial progenitors receive paracrine signals from the surrounding mesenchymal niche, which can modulate their ability to proliferate and differentiate. The pancreas consists of a variety of specialized epithelial cells, including endocrine and acinar cells, surrounded by a poorly defined heterogeneous mesenchyme. We hypothesise that different mesenchymal lineages define local instructive microenvironments, including cell–cell crosstalk, ECM and signalling molecules, which eventually trigger distinct differentiation programmes from pancreatic progenitors. Sc-RNA-sequencing has generated a transcriptional map of the pancreatic mesenchyme in the mouse embryo. Here, we will unravel the spatial architecture of the identified mesenchymal cell states, linking their position to emerging pancreatic cell identities. Next, we will assess if mesenchymal lineages with a distinct spatial address underlie unique niche regulatory functions, promoting acinar or &beta;-cell differentiation. Finally, we will study the organisation and function of the identified niche microenvironment(s) in human tissue and pluripotent stem cells. The proposed programme will yield novel insight into pancreas biology and will set the stage for manipulating combinatorial pancreatic niches - an important step towards engineering functional &beta;-cells for regenerative medicine applications.

Lay abstract: The pancreas is a complex organ comprised of a mixture of various cell types, including epithelial and mesenchymal cells. Pancreatic epithelial cells control vital functions, such as food digestion and regulation of blood sugar levels through insulin-producing cells. The pancreas is the target of incurable diseases: diabetes and pancreatic cancer. The crosstalk between pancreatic epithelial cells and the surrounding mesenchymal cells is fundamental for the organ formation and its functions. We previously discovered a high degree of heterogeneity within pancreatic mesenchymal cells. This proposal aims at answering the question whether this heterogeneity corresponds to functional diversity. We will address if mesenchymal cells at distinct locations create unique microenvironments that promote the formation and function of the adjacent pancreatic cell type. All findings obtained in the mouse will be validated and transposed onto human models. This will pave the way towards new possibilities of engineering functional pancreatic cells for biomedical applications.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: METABOLIC AND ENDOCRINE;GENERIC HEALTH RELEVANCE
Title: Immunomodulation of type I diabetes by pharmacologically-enhanced delivery of regulatory T cells
Funder: Diabetes UK

Abstract: A small subset of lymphocytes in the blood, the thymic regulatory T-cells (Tregs), specializes in preventing autoimmunity. Ex-vivo expanded Tregs offer a promising new avenue for the treatment of type 1 diabetes (T1D), when infused in large numbers into diseased individuals. A major problem with this approach is the high number of Tregs required for a beneficial effect, which makes this therapy very laborious and expensive. Treg migration to inflamed tissue is key to their immune-modulatory function. We have recently discovered that the glycolytic enzyme glucokinase (GCK) is instrumental for Treg migration in humans and mice, while it is not functional in conventional T-cells. Increasing GCK activity with the small molecule GCK-activator AZD1656 (a repurposed drug) enhances Treg migration to inflamed tissue thus reducing skin allograft rejection and the incidence of T1D in susceptible mice. This treatment does not affect Treg function. We predict that pharmacological GCK activation and enhanced Treg homing to pancreatic islets and draining lymph nodes will slow down and possibly stop beta cell destruction in early-onset T1D. We propose to conduct preclinical studies to develop this novel approach to therapeutic immunomodulation in T1D, with the view to rapidly progress to clinical trials.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: METABOLIC AND ENDOCRINE;INFLAMMATORY AND IMMUNE SYSTEM
Title: Thymic B cells; aggressors in Type 1 diabetes
Funder: Diabetes UK

Abstract: To protect pathogens from harming us, the immune system produces B and T cells that express receptors specific for the pathogen's molecules, and upon binding to the pathogen release weapons that destroy it. To mitigate inappropriate attack on our own tissues, B and T cell receptors are tested for reactivity to our own tissues; any 'autoreactive' cell is destroyed. In T1D, killing of autoreactive cells is defective leading to immune cells attacking insulin-producing beta cells. Recently, using animal models of T1D, we showed failure to destroy autoreactive immune cells was linked to abnormalities in the thymus; the organ where autoreactive T cells are destroyed. Prior to diabetes development the thymic environment nurtures inappropriate accumulation of autoreactive B cells that release weapons-termed antibodies- that co-ordinate destruction of the very cells whose job it is to kill autoreactive T cells. In this proposal we will build on this novel data. Using a series of immunological and molecular techniques we will define the cellular and molecular events by which the pre-diabetic thymic environment nurtures inappropriate development and retention of thymic B cells and the mechanism(s) by which intrathymic antibodies destroy mTECs. Finally, we will determine if a similar phenomenon occurs in man.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;INFLAMMATORY AND IMMUNE SYSTEM
Title: 2014 Doctoral Fellowship: Impact of structured education on psychological stress to overcome a barrier to injectable treatment for type 2 diabetes. A randomised controlled trial
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Background: Type 2 diabetes frequently requires the use of injectable treatments to control glycaemia. This step is often feared by patients and may be associated with significant psychological stress. Aim: To design, test and evaluate the impact of a structured education programme on psychological stress associated with initiation of injectable treatment in type 2 diabetes. Hypothesis: Structured group education delivered in advance of initiation of injectable treatment will alleviate psychological stress associated with this transition. Methodology: A two phase study will be conducted. Phase 1: will inform the design of the educational programme. A retrospective interrogation of the Diamond diabetes database to investigate current practice relating to commencing injectable treatment will be carried out in a sample of patient records. This phase will also involve focus groups with those recently commenced on insulin to explore their views regarding the topics to be addressed in the education programme and method of delivery. Phase 2: a randomised controlled trial will be conducted on 150 eligible patients with type 2 diabetes. Patients will be randomly allocated to control (usual care) and intervention group (structured group education). Demographic, anthropometric, dietary, clinical and psychological data [The Problem Areas in Diabetes Scale (PAID), the Hospital Anxiety and Depression Scale (HADS-A) and the Pearlin Mastery scale] will be collected at baseline (week 0, at recruitment), 12 and 24 weeks post course completion and at equivalent time points for control group. Data analysis: Primary outcome measure will be a reduction in the PAID Scale score between groups.


Research activity codes: 7.1 INDIVIDUAL CARE NEEDS
Health categories: METABOLIC AND ENDOCRINE;MENTAL HEALTH
Title: Understanding the role of obesity in the deterioration of skeletal muscle mass and quality in older age: New mechanistic insights
Funder: Dunhill Medical Trust

Abstract: Muscle loss in older age increases the risk of disability, institutionalization and early death. Given the growing number of older individuals in society, it is imperative that we understand the factors that cause age-related muscle loss so that we can develop strategies to prevent, or slow, this occurrence. Age-related muscle loss may be explained by a reduced muscle growth response to nutrition compared with younger persons. We recently demonstrated that this reduced muscle growth response in old age is worse in obese older individuals. Despite a poorer muscle growth response to nutrition and poorer muscle quality (i.e. high levels of fat within the muscle and lower relative strength) in obese older individuals, overall muscle mass and the size of individual muscle fibres is preserved to a greater extent than lean older individuals. We suggest that the protective effects of obesity on muscle mass may his may be due to the greater load placed upon the muscles of obese individuals during weight-bearing activities (i.e. walking to the shops, climbing stairs). To understand the role of obesity in the control of muscle mass and quality in older age, we will determine whether the muscle growth response to weight-bearing exercise (moderate-intensity walking) is greater in obese compared with lean older and young individuals. Secondly, we will investigate whether, and to what extent, the content, location and type of fat cells stored within the muscle are associated with muscle growth responses in these same individuals. This project will provide evidence that the muscle growth response to weight-bearing activity is greater in obese vs. lean older individuals, but muscle quality (relative levels of strength and fat cells within the muscle) will be much poorer. Therefore, these data will offer an explanation as to how the presence of obesity in old age may protect muscle mass per se, yet harm muscle quality. Ultimately, despite higher levels of muscle mass in obese older individuals, greater levels of fatty deposit in muscle fibres will, over time, cause reductions in muscle quality so great that it will render obese older individuals unable to perform adequate levels of physical activity to stave off disability and disease. The proposed work will therefore enhance our understanding of the role obesity on muscle health in older individuals, which will ultimately lead us to develop new ways to dramatically improve muscle health and quality of life in these individuals.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE;MUSCULOSKELETAL
Title: Randomised, double-blinded, placebo-controlled, adaptive design trial of the efficacy of acipimox in patients with Mitochondrial Myopathy (AIMM)
Funder: Medical Research Council

Abstract: Muscle involvement manifesting as fatigue, exercise intolerance, myalgia and muscle weakness is a major problem in adult patients with mitochondrial disease. The management of these patients remains challenging, not least because there are currently no interventions that provide a realistic prospect of cure. This represents a compelling unmet need and suggests that key aspects of mitochondrial dysfunction remain untargeted. Novel approaches to management have recently included pharmacological stimulation of Sirtuin 1 (SIRT1)-mediated mitochondrial biogenesis, by boosting levels of NAD+. This has been demonstrated to be a highly effective therapeutic strategy to correct the underlying biochemical defect and alleviate the clinical phenotype in animal models of mitochondrial disease, and studies in patients with diabetes has shown that this approach should also be effective in patients with mitochondrial disease. Acipimox, a nicotinic acid derivative and natural nicotinamide adenine dinucleotide (NAD+) donor, is a generically available drug currently licensed for the management of hypertriglyceridemia. Supplementation with acipimox, has been shown to have a direct effect on muscle and mitochondrial function by improving mitochondrial oxidative phosphorylation and metabolic capacity. This trial aims to repurpose acipimox as a potent stimulator of mitochondrial biogenesis and disease-modifying agent for patients with mitochondrial disease and muscle involvement. The primary outcome will assess change in muscle adenosine triphosphate (ATP) content of placebo and acipimox-treated patients, as well as improving function and quality of life.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE;MUSCULOSKELETAL