NIHRDataInsights/HRCSData huggingface dataset:
Title: Elucidating the functions of Pbx1 during pancreatic cell differentiation
Funder: Wellcome Trust

Abstract: Pbx1 is a TALE homeodomain transcription factor whose diverse regulatory function makes it indispensable for organogenesis (Selleri et al., 2019). Its activity is essential for early pancreatic development as embryos with homozygous deficiency of Pbx1 exhibit pancreatic hypoplasia and cell differentiation defects prior to death in utero at E15.5 (Kim et al., 2002). However, the basic mechanisms underlying the requirements for Pbx in mammalian pancreatic development remain largely unexplored. Using a conditional Cre-Lox system, I will focus on Pbx1 deletion in pancreatic epithelium at various stages of mouse development and in the adult pancreas to determine its role in maintaining pancreatic cell type identity. I will also establish a human induced pluripotent stem cell model to assess whether developmental mechanisms involving Pbx1 observed in mice are also conserved in humans. Here, I will use CRISPRi-Cas9 gene editing to reversibly inhibit Pbx1 at different stages of pancreatic cell differentiation. Lastly, I will construct a gene regulatory network of the pancreatic epithelium using chromatin immunoprecipitation and RNA sequencing data at various developmental stages to test Pbx1 targets both in vivo and in vitro. This project has great potential for advancing the field of diabetes research, disease modelling and cell therapies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE
Title: Decoding pulsing proteins in the pancreas
Funder: Wellcome Trust

Abstract: The ability to generate functional beta-cells in vitro to treat diabetes is still lacking. Therefore a more comprehensive understanding of the developmental mechanisms involved in the generation of human pancreatic endocrine cells is needed. Recently it has become clear that important proteins in many tissues are expressed in a dynamic manner (i.e. oscillations vs sustained protein expression) which results in different cellular outcomes. Here, I propose a novel approach to understand the key mechanisms of pancreas development by focusing on the protein dynamics of Ngn3, an essential transcription factor for endocrine differentiation. I will investigate for the first time in human cells how different protein dynamics are decoded mechanistically. I will manipulate endogenous Ngn3 protein dynamics using a CRISPR-controlled optogenetic technique and assess the effect on cell-fate decisions. To investigate how the cells interpret the different dynamics, I will use state-of-the-art single-cell techniques to determine how the chromatin architecture at Ngn3’s target genes change over time and controls the response to different protein dynamics. I will then assess if by altering the chromatin architecture I can control cell fate decisions. This will enhance our understanding of pancreas development and will inform on human differentiation protocols to beta-cells for clinical purposes.

Lay abstract: Diabetes is a growing global health problem with currently more than 415 million people worldwide affected. Diabetes results from the inability of the pancreas to produce insulin, as a result of the loss of the insulin-producing cells (beta-cells). One therapy for the disease is to generate these cells in the laboratory and then to supply them to the patients by transplantation. However, there are still problems in producing functional beta-cells in the laboratory and in large enough amounts. My proposed research is focused on understanding how one dynamic important molecule, Ngn3, controls the generation of beta-cells. I will investigate how I can change the way Ngn3 works in order to make more and better functioning beta-cells that can be used for clinical purposes.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE
Title: Insights into metabolic health and disease from human genetic variants with major functional impact
Funder: Wellcome Trust

Abstract: The metabolism of macronutrients is controlled by the interplay of key organs, including liver, muscle and adipose tissue, orchestrated by hormonal and other signals. Disturbances in this network are associated with metabolic disease. We will build on our experience of using human genetics to illuminate mechanisms of insulin resistance to enhance understanding of the molecular control of human metabolism and its dysfunction in a range of diseases. We will use three independent but related approaches, each of which will exploit the power of rare non-synonymous human genetic variants with major functional impact. 1. We will study rare mutations significantly associated with metabolic phenotypes in large epidemiological studies. 2. We will identify and study rare, functionally significant mutations in genes that are known from studies in cells and animals to be important for metabolic control but where little information is currently available in humans. 3. We will study humans with rare extreme metabolic phenotypes; continuing to discover new genetic disorders and adding to knowledge of genotype/phenotype correlation. Each approach will involve the deep phenotyping of cells and humans. Any required extension of work into transgenic murine models will be the subject of a bid for additional, independent funding.

Lay abstract: How the body handles its main sources of energy (carbohydrates, fats and proteins) is key to maintaining health. This job is shared between organs such as liver, muscle and fat and is co-ordinated by hormonal signals such as insulin. Diseases such as diabetes and heart disease occur when these systems malfunction. We have learned a lot about how insulin works through studying humans who carry genetic mutations that interfere with its action. We would like to build on thisexperience to take a broader look at the way the body handles its metabolic pathways and how they can go wrong in a variety of diseases. Our previous work has shown that we can turn research findings into better patient care and we hope to be able to do the same across a broader range of disease with our new programme of research.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE
Title: Antioxidant defence in adrenocortical cells
Funder: Medical Research Council

Abstract: Decades of research support the idea that oxidative stress (OS) initiates and promotes cardiovascular, neurologic, and immune-related conditions. OS may arise from an imbalance between the production of reactive oxygen species (ROS) and the detoxification of these species by antioxidant defence systems such as the glutathione and thioredoxin systems At present, relatively little is known about the contribution of individual enzymes to the redox metabolism in different cell types. We have discovered mutations in four antioxidant (AO) genes in patients with Familial Glucocorticoid Deficiency (FGD) a disease of adrenal resistance to ACTH and loss of cortisol secretion. This suggests that the adrenal cortex may be exquisitely sensitive to ROS and AO defence of primary importance to this cell type. Failure of AO defence leads to increased ROS, decreased glutathione ratios, steroidogenic acute regulatory protein reduction and hence reduced steroidogenesis. Our aims are; A Delineation of a larger spectrum of anti-oxidant genes involved in the pathogenesis of FGD by whole exome sequencing of 100 affected individuals to identify novel mono- or (possibly) oligogenic variants. B Assessment of the effect of knockdown of antioxidant genes in human adrenocortical cell lines (H295R and HAC15) on; i) ROS levels, glutathione ratio, STAR mRNA and protein levels ii) steroidogenic profiles iii) altered AO gene expression C To attempt to rescue the phenotype in knockdown cell lines i) by pharmacological intervention ii) by overexpression of another antioxidant system Understanding the mechanisms by which OS causes adrenal cell dysfunction could have a much wider indirect impact. Such knowledge may be instructive in the wide range of more prevalent human disorders associated with OS (listed above). Utilising knockdown adrenal cell lines as models for OS and AO treatment as proposed here could give us insights into more effective treatments for these conditions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE
Title: Factors associated with uptake of structured education for people with newly diagnosed type 2 diabetes.
Funder: Department of Health (England)

Abstract: Rheumatoid arthritis (RA) is a chronic condition with a large but finite set of treatment options. The number of potential sequences is very large, and an appropriate methodology for evaluating all potential sequences is required. An optimal sequence may not be appropriate for a specific patient. Incorporating contraindications, uncertainty and patient heterogeneity is essential.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);7.3 MANAGEMENT AND DECISION MAKING
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE
Title: Pattern Dependent Specificity of Glucocorticoid Signalling
Funder: Wellcome Trust

Abstract: Steroid hormones are the cornerstone of treatment in many areas of medicine including rheumatoid arthritis, asthma, inflammatory bowel disease, autoimmune disease, leukaemias and skin disorders. Unfortunately treatment with steroids results in many severe side effects including diabetes, depression and cardiovascular disease. It has recently become apparent that in healthy animals including man, the steroids secreted by the adrenal gland are released in short bursts, rather than being constant ly released. This results in peaks and troughs of steroid occurring throughout the day. We have now been able to show that each peak is associated with a significant response at the level of the liver and the brain. We believe that the pattern of bursts of steroid release from the adrenal is important in relaying steroid signals to the body and this is what we would like to test in our research programme. We plan to assess how different patterns of bursts affect different tissues, especial ly on metabolism (blood sugar regulation) and brain function (memory).


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE
Title: Evaluation of the role of Neuronatin in nutritional homeostasis and metabolic-inflammation
Funder: Wellcome Trust

Abstract: Obesity is an important risk factor for major illnesses that afflict mankind, including diabetes, heart disease, dementia and cancer. Therefore, the quest for new and effective treatments for obesity is of great significance. We and others have discovered that a gene called neuronatin (Nnat) found in parts of the brain that control appetite and in fat tissue, may be important in telling us when we are optimally nourished, along with the storage of excess food by the body as fat, and for the bo dy's response to the toxic effects of nutrient-excess. Surprisingly, despite the apparent importance of Nnat little is known about what it really does or how it works in health and disease. Our goal is to understand how Nnat works, particularly as interference with Nnat may be way of controlling obesity and its serious disease consequences. To achieve this goal we have created models in mice in which the Nnat has been experimentally removed either in the brain or in fat tissue so that we can understand the consequences of not having Nnat on control of eating, the toxic consequences for the body of too much food and the development of obesity and its allied ill-health problems


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE
Title: Non-transcriptional mechanisms of the human circadian clock.
Funder: Wellcome Trust

Abstract: The circadian clock allows us to anticipate the daily cycle of light and dark, and controls many aspects of human biology, such when we feel sleepy or when our digestive system is most active. Most people have experienced Jet Lag, when the clock is out of synchrony with our behaviour, but far more serious conditions such as cancer, heart disease and neurological disorders are linked with shift work, when the body clock is chronically disrupted. Since around 14% of the adult population engage in shift work, this makes understanding body clock mechanisms an important objective for improving human health. At present, most scientific descriptions of the clock revolve around inter-linked genes (in the cell's core, or nucleus) being turned on and off throughout the day, but we have shown that even red blood cells (cells without a nucleus) have circadian rhythms in protein activity. This suggests that the real picture is much more complex than is currently understood, and so needs to be st udied further. We have so far identified several evolutionarily ancient metabolic pathways that appear to be involved, and would use this opportunity to pursue this exciting discovery.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE
Title: Statistical methods for the analysis of genome-wide association and re-sequencing studies.
Funder: Wellcome Trust

Abstract: There is a clear genetic basis to many common human traits, such as height and diabetes, as evidenced by familial resemblance and aggregation of disease. However our understanding of the genetic component of many of these traits is poorly understood. There has thus been substantial recent investment in large-scale studies to discover how humans differ in their genetic make-up and to investigate how these differences relate to our characteristics and risk of disease. The aim of this proposal i s to develop novel statistical methods for the analysis of genetic data generated by these studies so as to maximise the potential of this investment. The methods will be applied to cutting edge studies of type 2 diabetes and obesity which both represent a considerable drain on public health resources. It is hoped that this will provide a better understanding of the genetic and biological basis of these traits, potentially leading to the development of novel drug therapies in downstream clinic al practice.


Research activity codes: 1.4 METHODOLOGIES AND MEASUREMENTS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE
Title: The alloimmune response to human induced pluripotent stem cells and their differentiated progeny in a humanised mouse model.
Funder: Wellcome Trust

Abstract: Stem cells have the ability to differentiate into a number of different cell types, including pancreas cells. Significant advances in stem cell research have made the concept of generating personalized cell therapies for a wide variety of degenerative diseases such as diabetes a realistic possibility. However, the reaction of the immune system to cells generated from stem cells remains to be clarified. After organ transplantation the immune system mounts a significant attack against non-self cel ls and organs, necessitating the use of immunosuppressive medication to avoid rejection. It is not clear whether the immune system will similarly mount a deleterious response against cells and tissues derived from stem cells. I intend to address this fundamental unanswered question by creating mice whose immune systems consist of human cells and characterizing their immune compartment. I will subsequently compare in these mice the human immune response to self or non-self adult tissues as well as pancreas cells that I will derive from stem cells generated from human skin. I hope that the findings from this study will make a significant contribution to the development of stem-cell based therapeutic strategies in the future.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE
Title: The Tayside Bioresource: Leveraging Electronic Medical Records to deliver personalised medicine.
Funder: Wellcome Trust

Abstract: We have recruited 40,000 individuals (10% of total population) to specific bioresources within Tayside. This includes 18,000 individuals recruited to the Wellcome Trust funded GoDARTS study of type 2 diabetes. The ability in Tayside to link these bioresources to comprehensive and detailed longitudinal clinical data has resulted in GoDARTS contributing significantly to international landmark studies of many traits including type 2 diabetes, obesity, lipids, blood pressure, and cardiovascular di sease. We are seeking funding to maintain these resources to optimise and promote their continued contribution to the international genomic community. This will require laboratory staff for physical sample management and data processing/database management staff to manage and curate the accumulating genomic and phenotypic data associated with the study. A second strand of the proposal is to expand the resource efficiently through pre-consenting the population for the retention of left over b lood from routine clinical testing as part of the NHS Scotland Health Register (SHARE). We aim to have consented DNA samples from 30% of the local population with genotype linked to the unique electronic medical record available in Tayside. This strategy will provide a stepping stone, through partnership with other national initiatives, for development of a Scotland-wide resource.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Investigation into the effects of elevated oxidative stress on wound healing in vivo
Funder: Wellcome Trust

Abstract: Body tissues, such as the skin, must be able to rapidly repair themselves in response to injury. However, some individuals (particularly those with underlying health conditions) suffer from debilitating ‘chronic’ wounds that fail to heal, which are often persistently infected. These non-healing wounds are poorly understood and represent a significant burden to healthcare systems and economies.Damaged tissues recruit immune cells to ‘clean’ the wound, removing dead cells and producing toxic oxygen molecules to kill invading germs. This inflammatory response is essential for normal wound healing. However, overproduction of toxic molecules could cause ‘collateral damage’ to our own cells (termed ‘oxidative stress’) and hinder repair. To combat this, we have evolved a powerful network of ‘biological shields’ to protect injured tissues, including antioxidant production. My work will explore whether defects in this protective machinery are responsible for the failure of infected/diabetic wounds to heal and whether we can rescue healing by boosting protection. For this, I will use the fruit fly (Drosophila), exploiting their translucency (and genetic tractability) to study wound repair live ‘in vivo’. In parallel, I will use ‘genetic epidemiology’ to investigate their clinical relevance, by seeing if variations in equivalent human genes have links to disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE;INFLAMMATORY AND IMMUNE SYSTEM
Title: Muscle resilience across the life course: from cells to society
Funder: Medical Research Council

Abstract: A prominent change associated with ageing is the loss of muscle mass and function. As muscle is critical for physical function and metabolic homeostasis, loss of muscle mass and function results in adverse outcomes and is the major cause of loss of independence in old age. Muscle ageing is characterised by a variety of molecular, physiological, and systemic changes, often overlapping and interdependent. Ageing related changes in muscle are not linear or consistent and there is considerable variation across aged populations. Some of the variability can be explained by fixed genetic factors, but much of the variation is due to an individual's physical and social environment, with factors such as physical activity, nutrition, and socio-economic background all playing a role. Although research has focused on understanding the determinants of muscle ageing, the complexity of the process requires a new, convergent approach. We need to move away from systems in isolation towards a holistic understanding of muscle ageing where molecular, physiological, organism and population level research is combined. The MyAge network will break down the silos associated with reductionist research, bringing together non-overlapping expertise, researchers, industrialists, and stakeholders, from musculoskeletal research, metabolism, regenerative medicine, 'omics, epigenetics, maths, data and social sciences, health inequity, biotech, and pharma, to understand the mechanistic pathways of muscle development, differentiation and decline. The MyAge network will: Create a national, interdisciplinary network in muscle resilience with international links identifying big questions and developing novel hypotheses Through secondments deliver training opportunities for next generation researchers and technicians. Develop a roadmap for muscle ageing research to inform policy development, targeting proactive steps to address muscle ageing and related health inequities and inequalities.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE;MUSCULOSKELETAL
Title: Integrative Modulation of Trafficking and Signaling of TRPA1 Channels for Sustained pain
Funder: Medical Research Council

Abstract: Chronic pain remains a widespread public health problem. This research aims to understand the mechanisms of chronic pain with a view to revealing novel approaches for a better treatment of chronic pain. TRPA1 channels have been implicated in many different types of chronic pain such as painful diabetic neuropathy (PDN). However, the precise mechanisms by which TRPA1 drives prolonged pain remain elusive. In PDN, sustained pain is due to increased membrane trafficking of TRPA1 and activated downstream pain signaling such as ERK1/2, because diabetic pain is prevented by blocking either TRPA1 or ERK1/2. We have discovered a protein in sensory DRG neurons essential for both the trafficking and signaling of TRPA1 channels. The objectives of this research are to establish the role and mechanisms of this protein in the modulation of TRPA1 trafficking and signaling and the contribution of this protein to sustained pain. To monitor TRPA1 trafficking, membrane TRPA1 will be assessed using three different methods: (1) western blot detection of membrane proteins isolated with special protein extraction reagents; (2) membrane protein biotinylation assay, and (3) immunostaining surface TRPA1 with immunocytochemistry. Function of TRPA1 in DRG neurons will be monitored using Ca2+ imaging. We will also use molecular biology and protein binding assays to probe protein-protein interactions and the trafficking mechanisms of TRPA1. To investigate pain signaling mechanisms, we will use western blot and immunohistochemistry combined with pharmacological approaches and genetic manipulations. We will also use current patch clamping to assess the excitability of DRG neurons deficient for the identified protein. Finally, we will assess pain behaviours of mice lacking this protein using Von Frey and Hargreaves tests to determine the role of this protein in chronic pain. Altogether, this research will reveal the novel mechanisms by which TRPA1 mediates sustained pain.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: GENERIC HEALTH RELEVANCE;METABOLIC AND ENDOCRINE;NEUROLOGICAL