NIHRDataInsights/HRCSData huggingface dataset:
Title: Genomic and functional characterisation of cell-type specific epigenetic and genetic mechanisms implicated in human obesity.
Funder: Wellcome Trust

Abstract: Regulation of gene expression by DNA methylation (5mC) in response to genetic and environmental risk factors is considered important to human obesity and type-2 diabetes (T2D) pathogenesis. Yet, difficulty finding causal 5mC changes in humans is limiting downstream clinical applications. I have discovered 5mC changes robustly associated with obesity and their predicted effector genes in human adipocytes. I have then refined these loci and genes using human genomics, cross-species transcriptomics and biological evidence to 3 top candidates for discovery of novel mechanisms of disease – the MEDAG, FGFRL1 and TXNRD1 loci. I will use sophisticated gene targeting to investigate the causal effects of the MEDAG, FGFRL1 and TXNRD1 genes on obesity and T2D in a mouse model of human disease, and detailed phenotyping to examine the pathophysiological mechanisms. In parallel, I will use functional and experimental genomics to explore the regulatory significance of obesity-associated 5mC sites on MEDAG, FGFRL1 and TXNRD1 gene expression, and the underlying epigenetic mechanisms, in human adipocytes. These complementary lines of evidence will establish whether locus-specific 5mC variations and subsequent gene expression changes impact on human obesity phenotypes, and may define epigenomic and molecular targets for new obesity and T2D therapies.

Lay abstract: Epigenetic switches on DNA turn nearby genes on and off without changing the underlying genetic code. These switches are implicated in many aspects of obesity and diabetes, but finding and proving which switches cause human disease is a major challenge. I have used innovative screening and refinement strategies to discover epigenetic switches in human fat cells that may contribute to obesity and diabetes, and genes these switches are likely to affect. I will investigate whether and how these genes cause obesity and diabetes by deleting each gene in a mouse model of human disease physiology. I will map the locations of the epigenetic switches to identify proteins with switch activating potential, then use DNA-editing tools to show that individual switches and proteins actively regulate their corresponding genes, all in human fat cells. With these convergent approaches, I aim to discover new mechanisms of obesity and diabetes and potential treatment targets.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Elucidating the genetic and environmental determinants of congenital hypothyroidism
Funder: Wellcome Trust

Abstract: I first identified mutations in the anion transporter SLC26A7 as a novel genetic cause of human and murine congenital hypothyroidism (CH), but its molecular role in thyroid hormonogenesis remains unclear. I will investigate SLC26A7 function in cultured primary thyrocytes, initially evaluating its role in pH regulation, seeking new insights into thyroid hormone biosynthesis. The incidence of CH with a normally-located gland-in-situ (GIS CH) is increasing, but its determinants are poorly defined. In a case-control study, I will investigate the roles of genetic variants, micronutrients (iodine, selenium, iron) and endocrine disruptors (perchlorate, thiocyanate and nitrate), in the pathogenesis of permanent and transient GIS CH. Confirmed involvement of environmental factors will have public health ramefications and mandate future trials of micronutrient supplementation for treatment or prevention of CH. The study will also provide insights into the aetiology of transient CH, a clinically important entity for which the cause is largely unknown. DUOX2/DUOXA2 mutations impair thyroidal H2O2 production, often causing transient CH. I will investigate whether maternal heterozygosity for DUOX2/DUOXA2 mutations in association with increased gestational demand for thyroid hormone biosynthesis, causes hypothyroidism during pregnancy. Gestational thyroid dysfunction would mandate future studies of childhood neurodevelopmental outcome and levothyroxine treatment in such patients.

Lay abstract: I first identified genetic defects in SLC26A7 as a novel cause of congenital hypothyroidism (CH), however, its function in the thyroid gland remains unknown. I will characterize its role in thyroid hormone biosynthesis using cultured thyroid cells, thereby providing new insights into thyroid hormone production. Increasing numbers of babies are being diagnosed with CH with a normally-sited but dysfunctional thyroid gland-in-situ (GIS). I will evaluate the contributions of genetic factors, micronutrient deficiencies (iodine, selenium), and exposure to endocrine disrupting chemicals (perchlorate, thiocyanate, nitrate) to GIS CH. A causative role for nutritional deficiencies or disruptors would have significant public health implications. CH due to DUOX2/DUOXA2 mutations often resolves in childhood, however, I will assess whether female mutation-carriers develop hypothyroidism during pregnancy when thyroid hormone biosynthesis increases. Thyroid dysfunction during pregnancy would provide a basis for future studies to evaluate childhood neurodevelopmental outcomes and effects of levothyroxine treatment in such patients

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Transforming the management of Urea Cycle Disorders using non-invasive breath ammonia monitoring
Funder: Innovate UK

Abstract: **Urea Cycle Disorders (UCDs) are genetic conditions which lead to severe lifelong disability and early death**. They cause a buildup of ammonia, which is toxic, and result in serious and permanent brain damage. They tend to go undiagnosed at birth until the onset of illness, before damage has already occurred. These conditions are very difficult to manage, requiring regular visits to specialist care centres, which is extremely stressful and disruptive to family life. It has been described as "like living with a time bomb". Currently, ammonia can only be measured effectively in the hospital. There is no way to manage these conditions in the patients' homes. Having a way for patients and families to measure and monitor their ammonia at home would lead to significant improvements in the management of UCDs, and lead to significant improvements in patient quality and quantity of life, while also reducing the burden on the healthcare system. **BreathDX is working with its regional partners, UWE Bristol, University of Bristol and University Hospitals Bristol and Weston NHS Trust to bring its AmBeR breath ammonia measurement technology to UCD patients**. AmBeR is a simple to use, non-invasive means of measuring ammonia levels using breath. It has the potential to eliminate the unpredictability of managing UCD, reducing the heavy care burden and costs associated with lost income and time spent accessing health services. It also has the potential to improve the quality and quantity of life of sufferers, by improving both acute and chronic care management. It would also reduce the burden on the health service, reducing costs and improving efficiency and workflow.


Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES
Health categories: METABOLIC AND ENDOCRINE
Title: Dia Beta Labs
Funder: Innovate UK

Abstract: Dia Beta Labs are a UK-based biopharmaceutical company focused on the development of novel treatments for Type 2 diabetes mellitus and obesity. Dia Beta Labs builds on over 30 years of academic success from its founding research group, the Diabetes Research Group (DRG) at Ulster University, Northern Ireland. Diabetes occurs when the pancreas does not produce enough insulin (Type 1 diabetes mellitus), or when the insulin does not enable the body's cells to take up glucose (Type 2 diabetes mellitus, T2DM). Diabetes currently affects 537 million adults globally, a figure projected to rise to 625 million by 2040\. Importantly, obesity driven T2DM accounts for over 90% of cases. In the UK, the NHS spends over £10 billion annually on diabetes, with over 80% of this spend attributable to the various complications of the condition, brought about through inadequate control. Therapeutic development is crucial to curb increasing prevalence and disease progression, not being achieved with currently available prescribing options. Successful development will benefit patients and the wider economy as a result. Dia Beta Labs employ an innovative, target-led, approach to therapeutic development, in the generation of novel therapies for diabetes and obesity. Our therapies address a clinically unmet need, acting directly at insulin-producing beta-cells of the pancreas to reverse cellular damage brought about in poorly controlled diabetes. Moreover, we are developing multi-effect therapies which safely reduce appetite in addition to improving insulin production and function. Such therapies can replicate the positive effects of gastrointestinal surgery, while not carrying the considerable risks associated with an operation. Dia Beta Labs are committed to transforming the lives of patients living with diabetes and obesity. The silent epidemic of these concurrent conditions is considered by the World Health Organisation to be one of the most major concerns to public health in the 21st century, due to the increased risk of heart attack, stroke and cancer in these patients. We believe our therapeutics provide a simple solution to a complex problem: Earlier, more effective and longer-lasting glucose control in diabetes reduces the incidence of complications and the economic burden these carry.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Investigating age-related splicing and its links to type 2 diabetes.
Funder: The Academy of Medical Sciences

Abstract: Splicing is a highly regulated biological process by which mRNA exons are spliced together to form gene isoforms. Changes in splicing can be caused by germline genetic variants as well as ageing, but the downstream combined effects of these changes on disease risk are not fully understood. I will catalogue splicing changes induced by age and known diabetes risk variants to identify potential isoforms that drive disease development. Firstly, I will evaluate gene expression in whole pancreas samples using long read Nanopore RNA sequencing from individuals from 20 to 80 years old, some of which were diagnosed with T2D at the time of donation. By sequencing complete transcripts we can explore errors in splicing that may lead to T2D and identify transcript profiles specific for age or disease status. Secondly, I will measure gene expression from pancreatic islets with available genetic information to evaluate how often genetic variants associated with T2D also cause changes in splicing in insulin producing cells. This project will i) improve our currently limited knowledge about how age-related changes in the pancreas as a whole may influence the risk of T2D; ii) identify new predictors for pancreas health status using isoform information; and iii) identify new candidate genes mediating the activity of T2D GWAS variants through splicing regulation.

Lay abstract: Age-related diseases, those with higher risk of development at older ages, are the most common causes of death in the UK. Type 2 diabetes (T2D) is one of these diseases, where an individuals’ pancreas fails to meet the body’s needs for adequate insulin production, meaning they lose control of their blood sugar levels. As we age, our cells change the way genes are active and some of those changes are similar to those of people that develop T2D. My research aims to understand similarities and differences in these two types of changes to understand why we are more likely to develop certain diseases as we age. This particular project will focus on understanding how RNA, the molecule produced by genes that sends instructions around the cell, matures in a process called splicing and how errors in this process can cause disease. For this, we will measure RNA molecules in the pancreas of young and old donors, some of which have been diagnosed with T2D. Using computational methods for data analysis, we hope to identify genes that change with age and disease. Combining this information with the DNA from those individuals, we will also be able to explore how having family members diagnosed with T2D influences your risk of developing the disease as you age.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Exploring the interplay of social and genetic factors influencing puberty timing
Funder: The British Academy

Abstract: Age at menarche is a marker of biological maturity for girls that has been associated with several indicators of economic development. Although puberty is highly regulated by genetics, this is not sufficient to explain the dramatic fall in pubertal timing occurred in the last century worldwide. A first implication of this change is the consequent extension of the reproductive lifespan. At the same time, early pubertal timing has been associated with higher risk of diseases, such as type-2 diabetes, cardiovascular diseases and breast cancer. It is therefore important to focus on the causes of this rapid change that at the societal level have not yet been fully understood. This research will fill the gap by studying the social and genetic factors affecting puberty timing by analysing data from different countries, spanning from middle and low-income countries to rich countries, and combining for the first time environmental and genetic information.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;1.2 PSYCHOLOGICAL AND SOCIOECONOMIC PROCESSES
Health categories: METABOLIC AND ENDOCRINE
Title: Preclinical validation of liver gene therapy for Maple Syrup Urine Disease
Funder: LifeArc

Abstract: This research aims to develop a new gene therapy for children with a severe metabolic illness called Maple Syrup Urine Disease (MSUD). A child born with MSUD can’t process certain amino acids (the building blocks of proteins), leading to a harmful build-up of substances in the body. Without treatment, a child can develop severe, life-threatening symptoms – including seizures and coma. Some children will also be at risk of brain damage and may have delays in reaching their developmental milestones. In the UK, newborn babies are usually screened for MSUD. Once diagnosed, they are started on a special low-protein diet. But many children will continue to experience episodes of amino acid imbalance, which can lead to irreversible brain damage. MSUD is caused by faults in one of three genes that together contain the instructions to build an enzyme that breaks down certain amino acids. The researchers are hoping to use a virus to permanently introduce a healthy copy of the affected gene into patient liver cells shortly after birth. This approach offers the potential to provide lifelong protection from MSUD by restoring normal amino acid breakdown in treated liver cells. The team will now test the safety and effectiveness of their new gene therapy in a laboratory model of MSUD, laying the foundations for a future clinical trial. If successful, the approach could be used to treat many other metabolic diseases that are rooted in the liver.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: METABOLIC AND ENDOCRINE
Title: A cluster randomised controlled trial of the effectiveness and cost-effectiveness of an obesity prevention intervention in primary school age children
Funder: Department of Health (England)

Abstract: AimTo assess the effectiveness and cost-effectiveness of a community-level multi-component intervention programme in preventing obesity in 6-7 year old children compared to usual practice.DesignA cluster randomised controlled trial using schools as units of randomisation and analysis.SettingLocal Education Authority maintained primary schools within the West Midlands.PopulationChildren age 6-7 attending primary schools in the West Midlands. Schools will be stratified according to urban vs. rural location proportion of pupils from ethnic minority groups and proportion of children entitled to free school meals (as a proxy for deprivation). Schools in each stratum will be randomly allocated to intervention or control armsInterventionA multi-component intervention programme will be delivered to schools in the intervention arm for one year. This programme consists of several elements; activities to increase the time spent doing physical activity within the school day participation in the ‘Villa Vitality’ programme (a programme that is delivered by an iconic sporting institution (Aston Villa Football Club) which provides interactive learning and opportunities for physical activity and healthy eating) healthy cooking sessions in school time for parents and children and provision of information to families signposting local leisure opportunities.Outcome measuresPrimary outcome measure: The difference in percentage of children categorised as normal weight overweight and obese in control compared to intervention schools. Overweight and obese will be defined by BMI using cut-offs at the 85th and 95th percentiles on the UK 1990 reference charts for BMI centiles for boys and girls. Secondary outcome measures: As BMI has limitations as a proxy measure for adiposity other indirect measures of adiposity will be undertaken including waist circumference skinfold thickness and bioimpedance analysis. In addition blood pressure 24 hour dietary intake and physical activity will be assessed. Health-related quality of life and body image will also be assessed.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: METABOLIC AND ENDOCRINE
Title: The REPOSE (Relative Effectiveness of Pumps Over MDI and Structured Education) Trial
Funder: Department of Health (England)

Abstract: In Type 1 diabetes the aim of insulin therapy is to keep blood glucose close to normal to prevent longterm complications without severe hypoglycaemia (low blood sugar) Insulin is generally administered by multiple injections with the dose adjusted according to eating and exercise. Insulin can now also be administered using a pump device filled with insulin that can continuously supply both the insulin needed for basal metabolism throughout the day and to cover meals. The use of pumps is expensive compared to injections but the potential advantages include better glucose control reduced risk of hypoglycaemia and a more flexible lifestyle. Although previous trials have shown some benefit the improvements have often been modest and it is unclear whether these benefits are in part due to the structured education that accompanies pump training. There have been no trials in adults that have compared pump treatment with injections where the same structured education in insulin adjustment has been given so the added benefit of the pump technology is still unclear. There is a need to establish this and identify patients who benefit the most. The Department of Health could then calculate the proportion of adults that would benefit from pump therapy and guide the commissioning bodies that are expected to provide funding. The aim of the trial is therefore to establish the additional benefit of pump therapy over high quality structured education including quality of life and cost effectiveness. 280 participants will be recruited from seven UK centres and randomised to a one week education course with multiple injection or pump treatment. For each participant biochemical quantitative and qualitative psychosocial measures and health economics will be assessed at baseline (before the course) 6 months (after the course has ended) 12 months and 24 months. .


Research activity codes: 6.3 MEDICAL DEVICES;6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Randomised controlled trial of continuous subcutaneous insulin infusion compared to multiple daily injection regimens in children and young people at diagnosis of type I diabetes mellitus
Funder: Department of Health (England)

Abstract: Background: Type I diabetes mellitus (TIDM) is a common disease of childhood. The daily management of TIDM is burdensome requiring daily injections of insulin blood glucose monitoring and dietary manipulation. However it is the long term vascular complications of the disease which have greatest impact on morbidity mortality and well being. Aim: To investigate two methods of insulin delivery [multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII)] during childhood and adolescence to examine the impact of treatment modalities on predictors of vascular complications of TIDM adverse events and quality of life. A health economic evaluation will also be undertaken. Study Design: Randomised controlled study with in built pilot. During the six month pilot study 30 patients will be recruited from four centres. The full study will progress if = 50% of patients approached are successfully recruited and if there are no significant differences between those who accept and those who decline with regard to age gender and social deprivation score. Patients and Methods: 316 participants aged 6 months - 15 years will be recruited at diagnosis of TIDM from 10 UK centres. Randomisation to CSII or MDI will be on a 1:1 ratio stratified for age and centre. The following observations will be made at baseline 3 6 9 and 12 months: HbA1c height weight. Quality of life and health economic measures will be made at baseline 6 and 12 months. Insulin doses will be assessed at 3 6 9 and 12 months.


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