NIHRDataInsights/HRCSData huggingface dataset:
Title: Towards a novel treatment targeting obesity in women with polycystic ovary syndrome (PCOS)
Funder: Medical Research Council

Abstract: Obesity worsens the symptoms and consequences of PCOS, but women with PCOS find losing weight difficult. This is not because of increased energy intake but rather a consequence of weight-independent reduction in postprandial energy expenditure (PPEE). There is an unmet need for treatment that improves postprandial thermogenesis (PPT) in PCOS to facilitate weight loss. The ASRM-ESHRE consensus on women's health highlights the need for strategies to tackle obesity in PCOS. The solution may be intranasal insulin (INI) with food, which increases central insulin signalling without systemic effects. This drives sympathetic activation of subcutaneous adipose tissue (SAT) to augment thermogenesis. This solution has been developed and successfully tested in an ovine model of PCOS with an identical PPT deficit. However, we do not know if the reduction in PPT in women with PCOS has the same mechanistic underpinnings. As INI is well-tolerated, we will use it as a tool to examine whether it increases sympathetic drive to SAT, alters SAT function towards increased thermogenesis and increases PPEE in women with PCOS, and determine if these effects are PCOS-specific. We will study obese women with and without PCOS. The effect of INI on PPEE will be assessed by indirect calorimetry after being fed a standard meal on two occasions with either intranasal placebo or INI in random order. SAT microdialysis will be used to assess the sympathetic thermogenic drive. Biopsies will be used to examine the effect of PCOS and INI on SAT gene expression and mitochondrial function. The primary outcome is the effect of INI on PPEE in obese women with PCOS. Secondary outcomes will determine if this is PCOS-specific and give additional mechanistic information of the effect of PCOS and INI on SAT function. Proof of concept will facilitate industrial partnership and support the development of a clinical efficacy trial of INI as a novel repurposed solution for weight management in women with PCOS.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Circadian iron metabolism, implications for health, and response to inflammatory disease.
Funder: Medical Research Council

Abstract: We recently discovered that the liver-derived hormone hepcidin, which controls iron absorption, and mobilisation, lies under strong circadian control. In inflammation it remains circadian, but with a phase shift resulting in an earlier peak. Indeed, this may explain why iron is absorbed from the diet more efficiently at specific times of day. Iron metabolism in cells is closely linked to redox state, and an ancient function of the circadian clock is to regulate cellular redox state. Indeed, dietary iron manipulation results in changes in the circadian regulation of glucose metabolism in the liver. Heme abundance, and redox status may directly regulate the core clock factor REVERBa. We now propose to investigate:- 1. How iron metabolism regulates the liver metabolic clock. Here, we will delete hepcidin from the liver, post-natally, and investigate the function of the liver circadian system, using primary cell culture, and whole animal recording. As hepcidin is produced by hepatocytes, and acts on myeloid cells we will use single cell RNA-Seq to determine the cell-type specific impacts of hepcidin loss. We will investigate the downstream consequences for glucose and lipid metabolism, using dynamic metabolic tests, and metabolomics screening. 2. How timing affects iron metabolism. Here we will make a new mouse which has hepcidin driven from a non-circadian promoter. In this way we can study iron metabolism by time of day in the presence of a circadian, and a non-circadian hepcidin driver. This will determine why hepcidin, and iron are so strongly circadian, and identify the role of chronotherapy for targeting disorders of iron metabolism. 3. How chronic inflammation regulates hepcidin and iron metabolism to drive liver function. Here we will use an inducible, liver-specific hepcidin knockout, and examine how chronic inflammatory arthritis impacts on liver circadian function. We will return to some of the analytical approaches developed above.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Investigating the role of Viperin in beta cell survival and the development of type 1 diabetes.
Funder: Medical Research Council

Abstract: Aim 1: Determine if genetic loss or gain of Viperin expression alters disease onset or progression in a model of T1D. We will make genetic loss-of-function (Rsad2KO) and gain-of-function (Ins1-Rsad2KI) mice on a diabetes susceptible NOD/ShiLtJ background, to enable objective assessment of the impact of Viperin levels on type 1 diabetes onset/progression and beta cell decline. Aim2: Investigating the role of Viperin in human beta cell survival and function. Human islets will be exposed to cytokines ex vivo, with or without knock-down or overexpression of Viperin. An in situ hybridisation approach will be used to screen fixed human T1D pancreatic sections (and non-diabetic controls) for Viperin expression. Aim 3: Determine if enhancing Viperin expression in beta cells improves islet transplant success in mice. We will transplant our mouse islets overexpressing lenti-Viperin or lenti-GFP into STZ-induced diabetic recipient mice, either as an allogeneic or syngeneic graft. This will enable us to test if sustained Viperin expression can improve islet transplant survival and function. Aim 4: Investigate the cellular signalling mechanisms by which Viperin regulates cytokine-induced beta cell apoptosis. Finally, we will investigate the roles of UPR signalling/ER stress and oxidative stress, in coupling beta cell inflammation, Viperin expression and apoptosis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: MICA: Clinical validation of a non-invasive diagnostic test for adrenal insufficiency using comparative pharmacodynamic equivalence
Funder: Medical Research Council

Abstract: Cortisol is an essential stress hormone and failure of production, adrenal insufficiency (AI), is associated with significant mortality due to adrenal crisis. The common causes in the Western world are iatrogenic adrenal suppression from steroid use, pituitary gland pathologies & autoimmunity; and globally TB & AIDS. The Short Synacthen Test (SST) is the diagnostic test of choice for AI. It is invasive (cannulation/blood sampling) & resource-intensive (skilled personnel/daycare admission), resulting in raised thresholds for investigation & delayed diagnosis. Globally there is an unmet need for a non-invasive cost-effective test. We are developing an innovative needle-free SST, using Synacthen (tetracosactide) mixed with the nasal drug enhancer chitosan. This novel nasal formulation, Nasacthin, combined with saliva used to measure the glucocorticoid response (salivary cortisol & cortisone), renders the test non-invasive. PK studies (60 healthy volunteers) have demonstrated reproducible plasma & salivary results. In 2018 we gained MHRA Scientific Advice on the clinical regulatory pathway to Market Authorisation (MA) for the Nasacthin formulation. Further MHRA advice (2021) agreed our design for the clinical studies required for MA which are: 1) demonstrating comparative pharmacodynamic (PD) non-inferiority of Nasacthin to 250mcg IV Synacthen in healthy adults & children; and 2) a PD study demonstrating adrenal function testing with Nasacthin is able to correctly diagnose patients with AI by calculation of positive percent agreement with the IV SST. These studies will facilitate commercialisation by providing the clinical data for the regulatory approval of Nasacthin, giving industry sufficient confidence to develop the full data package for MA. The route to market will be through a licence deal to a pharmaceutical company bringing patient benefit through a streamlined clinical care pathway, yielding timely diagnosis and a better tolerated test, especially in children.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE
Title: Unravelling the tissue-specific geography of protein aggregation in human disease
Funder: Medical Research Council

Abstract: Type 2 diabetes (T2D) is a major societal concern, having reached pandemic status in the industrialized world. Around 5m people in the UK live with T2D, at an annual economic cost to the NHS of >£10 billion. Increasing evidence suggests that the aggregation of human islet amyloid polypeptide (hIAPP) is aetiologically important in beta-cell dysfunction/failure. hIAPP is a peptide hormone which is co-secreted with insulin by beta-cells in pancreatic islets. hIAPP aggregates are found in >90% T2D cases, but we do not understand the role of hIAPP aggregation as a driver of decreased circulating insulin. The molecular detail of aggregation is also poorly understood, and we lack precise knowledge of the in vivo structure of hIAPP aggregates, the nature of any oligomeric states on/off pathway to amyloid fibrils, the composition of aggregates, or the interactome of aggregates in and around beta-cells. Crucially, we do not understand how things change over time/space, Or whether there is a difference in aggregation near to, e.g. islet microvasculature? We will establish a new interdisciplinary collaboration which will use a nanopipette to perform localized extractions from human pancreatic tissue. This device will sample from specific regions of individual cells, allowing us to survey and sample tissue cell-by-cell, or more widely, assessing e.g. the number and/or structure of aggregates/oligomers . We will investigate their structure and cellular context using cryo-EM/ET, and for their oligomeric state, post-translational modifications and interactomes using mass spectrometry. Crucially we will create a unique resource of tissue from people with T2D, with detailed pathology, and integrate our discoveries into a whole pancreas pathology atlas linked to detailed clinical data/pathology, blood samples and a tissue bank assembled from organ donors with/without diabetes - integrating molecular, tissue and whole patient understanding.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: HappierFeet-Disrupting the vicious cycle of healthcare decline in Diabetic Foot Ulceration through active prevention: The future of self-managed care
Funder: Medical Research Council

Abstract: Diabetic foot ulcers (DFUs) are common, chronic and cost the NHS £1Billion annually. Up to 25% of patients with diabetes develop a DFU within their lifetime. Healing is slow and 40% of patients re-ulcerate within 12 months. DFUs frequently recur and lead to amputation and/or death, with a 40% mortality rate at 5 years. DFUs are more common in people who are socially and economically disadvantaged. The physical and emotional burden of ulceration is considerable: 32% are depressed and this is related to a 3-fold greater risk of mortality. Gait is often maladaptive in this group, overloading parts of the foot, making movement painful/unsafe, and they are scared of movement. They often feel hopeless about the future, as it's not currently possible to prevent DFUs. A consequence is a downward vicious cycle of reduced movement, self-efficacy and mood, which is thought to negatively impact patient ability to engage in preventative behaviours for DFUs and increase chances of re-ulceration, but also has significant potential to increase other disorders which are influenced by lack of physical activity/low mood, e.g. pain, cardio-metabolic disorders, and cancer. This project proposes to build and expand on current smart insole technologies for the detection of Diabetic Foot Ulcers, utilising a multiple sensor-based approach for their identification. A smart insole with integrated pressure, temperature, acoustic and sensors which measure how someone walks will identify early indicators of ulceration and when movement is appropriate/ inappropriate. The smart insole will respond to these inputs and adjust the foot, and hence the way someone walks, through embedded actuators, to support better, safe and comfortable movement. The smart insole will alert the user to potential problems, through a smartphone, enabling self-management; promoting users to check their foot and seek medical attention as required. Although data sharing with the cloud to facilitate community self-management and to inform clinical decision-making is beyond the scope of this project, this research will lay the foundations for future proofing the security and privacy of highly sensitive information against advancements in quantum computing. This project will seek to understand and overcome the barriers of technology adaptability, acceptability and adoption for users and their social networks (friends, family etc). This smart insole can break the vicious cycle by increasing self-efficacy to self-manage Diabetic Foot Ulcers and to be more active, thus impacting across multiple illnesses which respond to physical activity.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;7.1 INDIVIDUAL CARE NEEDS
Health categories: METABOLIC AND ENDOCRINE
Title: Targeting endothelial-erythrocyte glycocalyx exchange for the novel diagnosis and treatment of renal disease
Funder: Medical Research Council

Abstract: The endothelial glycocalyx (EnGlx) is composed of interwoven proteins and sugars. It lines blood vessels, limiting permeability to macromolecules, regulating local blood flow and clotting, and restricting the interaction with circulating cells. In diabetes damage to glomerular EnGlx results in increased albumin leakage. During the earliest phase of diabetic nephropathy (DN) the renal tubules re-absorb and metabolise filtered albumin, preventing detectable albuminuria. By the time albuminuria is detectable extensive damage has occurred and the potential impact of reno-protective strategies (e.g. angiotensin converting enzyme inhibition) are limited. However, DN does not develop in all diabetic patients. I believe that if we could detect Glx damage we could identify the subset of patients at the highest risk of subsequently developing DN. I have developed a lectin-based method to assess the EnGlx on fixed human tissue and shown that patients with DN have a damaged EnGlx. I have since developed a blood assay to detect Glx damage and shown that it accurately predicts glomerular Glx changes and directly measured glomerular albumin permeability in rats. In addition, I have demonstrated a novel mechanism of Glx damage and repair using an in vitro human cell model. A patent covering this novel work is being submitted. I now plan to test the predictive power of my test in human diabetic patients by collaborating with the BEAt-DKD research team in Exeter whilst investigating its effectiveness in patients with minimal change nephrotic syndrome by establishing my own study in Bristol. I will also continue work on the novel mechanism of Glx repair I have discovered, testing if it can be harnessed to deliver 'pre-formed Glx' selectively to areas of endothelial damage. In addition, I will work with the computer sciences department to develop software to further automate my assay, ensuring that it can be used in large scale trials and clinical practice in the future.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE
Title: Recapitulating beta cell development adjacent to the islet vascular niche to advance beta cell replacement therapies for type 1 diabetes.
Funder: Medical Research Council

Abstract: Type 1 diabetes (T1D) can be treated long-term by beta cell replacement therapies. To generate a renewable source of beta cells, human pluripotent stem cells (SCs) can be differentiated to pancreatic progenitors/endodermal cells (SC-PP/PEC) or beta cells (SC-beta cells) which are currently in clinical trials. However, the two major challenges are: (i) poor cell survival post-transplantation due to the lack of timely vascularization that leads to low cell mass, and (ii) the suboptimal function of SC-beta cells due to their immature phenotype. I have previously established that co-transplantation of microvessel fragments containing endothelial and perivascular cells with pancreatic cells can significantly improve cell survival, enhance beta cell function, and induce SC-beta cell maturation. Therefore, in this proposal, I aim to recapitulate the islet vascular niche in vitro to simultaneously achieve SC-beta cell maturation and vascularization. First, I will characterize the islet vasculature by single cell spatiotemporal analysis of the human isles. Further using multi-disciplinary approaches, I will recapitulate the native vasculature in vitro for co-culture with the SC-beta cells. To study various aspects of the vasculature, I will utilize a step-wise strategy to model vascular cell- beta cell contact, which will be complemented with extracellular matrix components, vessel tube formation, shear flow, and arteriovenous directionality. I will study beta cell development, maturation, and function at each step. Through these studies, I will develop vascularized and mature beta cells and assess their potential for engraftment post-transplant and normalization of blood glucose in T1D animal models.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: METABOLIC AND ENDOCRINE
Title: Olipudase alfa for treating acid sphingomyelinase deficiency (Niemann-Pick disease type B and AB) [ID3913]
Funder: Department of Health and Social Care

Abstract: Niemann-Pick disease is a group of inherited autosomal recessive metabolic disorders. Niemann-Pick types A, B and AB (also collectively known as Acid Sphingomyelinase Deficiency[1] ) are caused by mutations in the SMPD1 gene. This gene mutation leads to a deficiency in an enzyme called acid sphingomyelinase, which breaks down a naturally occurring fatty substance called sphingomyelin. The deficiency in this enzyme leads to accumulation of sphingomyelin in cells throughout the body. In Niemann-Pick types A, B and AB, build-up of sphingomyelin occurs in the liver, spleen and lungs. _x000D_ _x000D_ Signs and symptoms of Niemann-Pick type A develop within the first few months of life and include feeding difficulties; prolonged jaundice; enlargement of the liver and spleen and progressive loss of early motor skills, including ataxia. Signs and symptoms of Niemann-Pick type B usually occur in childhood and include fatigue and exercise intolerance, enlargement of organs, usually starting with the liver or spleen; poor growth; puberty delay; susceptibility to respiratory infections; bleeding problems and bone pain. Life expectancy for people with Niemann-Pick type B is highly variable depending on the severity of symptoms. Some people present with a type AB variant, with symptoms consistent with both type A and B. Symptoms of type AB can range from moderate to severe[2] . _x000D_ _x000D_ It is estimated that around 1 to 2 people are diagnosed with Niemann-Pick type A, B or AB per year. Most are diagnosed in childhood, although it may be difficult to diagnose according to type in young infants. It is estimated that around 40 to 50 people are living with Niemann-Pick type A, B or AB in England, with most of these people having type B disease._x000D_ _x000D_ There are currently no specific treatments or cure for Niemann-Pick type B or AB. However, people with Niemann-Pick type B or AB will benefit from supportive or palliative treatments. This includes treatments for managing the symptoms of the disease, including blood transfusions, respiratory support, medication for lipid control and analgesia. Some people with late-stage liver disease caused by the disorder may be offered a liver transplant._x000D_ _x000D_ References_x000D_ 1 National Organization for Rare Disorders (2019) Acid Sphingomyelinase Deficiency. Accessed June 2022_x000D_ 2 Patient UK (2016) Niemann-Pick Disease. Accessed June 2022

Lay abstract: To evaluate the benefits and costs of olipudase alfa within its marketing authorisation for treating acid sphingomyelinase deficiency (Niemann-Pick disease type B and AB) for national commissioning by NHS England.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Somatrogon for treating growth disturbance in children and young people aged 3 and over [ID5086]
Funder: Department of Health and Social Care

Abstract: Human growth hormone is produced by the anterior pituitary gland. The synthetic form is called somatropin (recombinant human growth hormone). Human growth hormone is essential for normal growth in children. It increases growth by a direct action on the growth plates (the area between the epiphysis and the diaphysis within which bone growth occurs) and by production of insulin-like growth factors (mainly in the liver). Growth hormone also has important effects on the metabolism of proteins, lipids and carbohydrates, not only during childhood, but also throughout adult life. _x000D_ _x000D_ Growth hormone deficiency occurs when the pituitary gland does not produce enough human growth hormone and is the most common endocrine cause of short stature. Growth failure in children can also be a result of growth hormone deficiency, but also occurs in children with Turner syndrome, chronic renal insufficiency (CRI), short stature homeobox-containing gene (SHOX) deficiency, and in children born small for gestational age.Growth hormone deficiency may also be associated with deficiencies in several pituitary hormones arising from hypopituitarism, tumours in the central nervous system, cranial irradiation or other physiological causes. _x000D_ _x000D_ The prevalence of growth hormone deficiency is estimated to be between 1 in 3500 and 1 in 4000 children.[1] In about half of the children with growth hormone deficiency (50%), the cause is unknown (idiopathic growth hormone deficiency).[1] _x000D_ _x000D_ Somatropin (recombinant human growth hormone) is currently the only active pharmacological treatment option for growth failure in children with growth hormone deficiency. It is administered as a daily subcutaneous injection. The place of somatropin in the treatment pathway depends on the child's particular condition, age at diagnosis and the licensed indications of each of the seven somatropin preparations used in UK practice._x000D_ _x000D_ References_x000D_ 1. National Institute for Health and Care Excellence. Human growth hormone (somatropin) for the treatment of growth failure in children (2010). Accessed June 2022.

Lay abstract: To appraise the clinical and cost effectiveness of somatrogon within its marketing authorisation for treating children and adolescents from 3 years of age with growth disturbance due to insufficient secretion of growth hormone.

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