NIHRDataInsights/HRCSData huggingface dataset:
Title: Regulation of HIPK3 by acetylation. Implications on diabetes
Funder: Diabetes UK

Abstract: Insufficient beta cell function is a common feature of all diabetes. Understanding the molecular pathways regulating beta cell survival/function is vital to find ways to prevent and reverse the disease. HIPK3 is a kinase whose relevance in beta cell function/survival and in diabetes has been clearly demonstrated in the last years. We have recently used mass-spectrometry to detect at least three residues in HIPK3 modified by acetylation. Importantly, these residues lie within critical domains of the protein. These include the active site of the kinase itself, but also a conserved nuclear localisation signal (NLS). Our hypothesis is that these modifications are highly likely to affect the activity and/or subcellular localisation of HIPK3 and may thus be critical determinants of its function in beta cell. In this proposal we plan to study how acetylation controls HIPK3 activity in beta cells, and the outcomes of this regulation. Furthermore we want to determine the conditions that lead to these acetylation event(s) in beta cells, and to analyse the presence of this modification in vivo, using mouse and human tissue. In order to do this, it is critical that we generate and characterise antibodies, which can recognise specific acetylated sites within HIPK3. These antibodies will be the first research tools available anywhere to study HIPK3 modifications in vivo.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Investigating the role of TRPV4 in diabetic bladder dysfunction
Funder: Diabetes UK

Abstract: People with diabetes commonly suffer with diabetic bladder dysfunction (DBD), causing urinary urgency and incontinence, and impairing quality of life. The mechanisms underlying DBD are poorly understood, making treatment difficult. Mouse models of diabetes show DBD, characterised by overactivity in the bladder smooth muscle, in both intact bladders and in muscle strips studied in organ baths. Mice lacking the ion channel TRPV4, a stretch sensor within the bladder epithelium, also show changes in bladder contraction that mimic those seen in DBD. Our objectives in this project are to explore the link between DBD in a mouse model of type 1 diabetes and TRPV4 function, to identify whether normal TRPV4 functions are impaired during diabetes, or whether the amount of the protein is altered. We will induce diabetes in normal mice and mice without TRPV4 and then monitor their patterns of urination. Cystometry will be performed to monitor bladder behaviour in situ. We will also collect bladder tissue, to study muscle function and measure the amount of TRPV4 expression at the protein and RNA level. By increasing understanding of DBD we hope to discover new targets for treatment, which may also be beneficial in treating other causes of overactive bladder.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: S-acylation and the regulation of calcium-activated (BK) channels in pancreatic beta cells (invited resubmission)
Funder: Diabetes UK

Abstract: Calcium-activated (BK) potassium channels play a critical role in controlling insulin release through the regulation of electrical excitability of pancreatic beta-cells. Indeed, loss of BK channel function leads to a reduced glucose tolerance, but normal insulin sensitivity, associated with reduced glucose stimulated insulin release from islets. In human beta-cells, BK channels are responsible for action potential repolarization and reduced activity of these channels leads to stimulation of insulin secretion. Mechanisms that control BK channel activity and/or surface expression thus represent fundamental regulators of beta-cell function. We have recently identified that S-acylation (palmitoylation), a reversible post-translational lipid modification of proteins, controls BK channel trafficking and activity and that pancreatic BK channels are endogenously palmitoylated. However, although S-acylation is dynamically regulated, including by high glucose and fatty diets, the role of palmitoylation in controlling beta-cell function is poorly understood. We will investigate the regulation, and functional role, of BK channel S-acylation in beta-cell physiology. These studies should elucidate novel and fundamental mechanisms that underpin pancreatic beta-cell physiology and characterize S-acylation as a new therapeutic target for diabetes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Investigating environmental influences on development of Type 1 diabetes
Funder: Diabetes UK

Abstract: Type 1 diabetes is characterised by destruction of insulin-producing beta cells by cytotoxic CD8 T cells. We will test the hypothesis that molecular mimicry, whereby a microbial peptide may have similarity to a beta-cell peptide and stimulate T cells to target islet antigens and destroy beta cells, is important in disease development. Gut bacteria influence developing T cells and can alter the incidence of diabetes in mice. This project will show that CD8 T cells recognising peptides of IGRP can be activated by similar bacteria-derived peptides to cause diabetes. In addition, identifying these peptides and bacteria may enable us to develop a new probiotic therapy to help prevent diabetes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Exploring targeted nutritional interventions to prevent diabetes
Funder: Diabetes UK

Abstract: While lifestyle interventions prevent the development of diabetes in subjects with Impaired Glucose Tolerance, there is no evidence that they are effective in people with isolated-Impaired Fasting Glucose. Subjects with i-IFG develop diabetes at the same rate as people with i-IGT, therefore targeted diabetes prevention may be required to reduce the incidence of diabetes. Our pilot studies have demonstrated that the fermentable carbohydrate inulin selectively improves fasting insulin sensitivity, while promoting early insulin and GLP-1 secretion. Since subjects with i-IFG have fasting insulin resistance and reduced early insulin secretion, fermentable carbohydrates such as inulin may represent a targeted intervention to prevent the development of diabetes in subjects with i-IFG. In this study 3 groups: i-IGT, i-IFG and i-IFG + 30g inulin per day will undergo a very-low-calorie-diet aimed at losing 5-7% of their body weight. At baseline and following the 6-week diet period, all subjects will undergo a Meal Tolerance Test, where fasting and post-prandial glucose and insulin measures will be taken at frequent intervals up to 120 minutes. The primary outcome will be fasting glucose, the secondary outcomes will be fasting insulin, insulin secretion index, tAUC glucose, tAUC insulin and body weight.


Research activity codes: 6.7 PHYSICAL
Health categories: METABOLIC AND ENDOCRINE
Title: Validation of Y receptors as targets for the maintenance of beta cell mass
Funder: Juvenile Diabetes Research Foundation

Abstract: Peptide YY (PYY) is a gut hormone originally isolated from porcine intestine. It is present in fetal and adult pancreas, but its role in this organ is not well understood. We recently demonstrated that ablation of PYYexpressing cells in the adult mouse leads to a catastrophic disruption of islet architecture and beta-cell destruction, with consequent development of insulin-dependent diabetes mellitus, suggesting that PYYexpressing cells may provide trophic support to beta-cells. Furthermore, we demonstrated that beta-cell loss was arrested by administration of X-PYY, a long acting analogue of PYY which has high affinity for Y1 and Y2 receptors. X-PYY was also as effective as exendin-4, a long acting analogue of glucagon-like peptide 1 (GLP-1), at ameliorating streptozotocin (STZ)-induced diabetes. We have subsequently demonstrated that mouse and human islets do not express mRNA encoding Y2 receptors, so the beneficial effects of X-PYY must occur via Y1 activation. We have also found that activation of Y1 receptors can prevent cytokine-, STZ- and peroxide-induced apoptosis of MIN6 beta-cells and Y1 activation has been shown to stimulate proliferation of beta-cells in isolated mouse islets. Type 1 diabetes results from autoimmune destruction of islet beta-cells, which decreases the total number of cells capable of secreting insulin. Therefore, two important therapeutic strategies are the prevention of beta-cell death and the stimulation of beta-cell replication in order to regenerate the lost beta-cells. Taken together, our data and the published literature -for the first time - identified Y receptors as potential targets for the preservation of beta-cell mass. We consider that they may be novel targets for the treatment or prevention of Type 1 diabetes. In the current proposal we will capitalize on these JDRF Strategic Research Agreement (SRA) - Validation of Y receptors as targets for the maintenance of beta cell mass - 2013 page 4 of 6findings and address the following questions. Which Y receptors modulate beta-cell mass? Do Y receptors stimulate proliferation or prevent apoptosis or both? What are the intracellular mechanisms employed? Can the Y receptor system be targeted to prevent disease progression? Are these same systems present in human tissue? Answering these questions will identify which Y receptors are novel targets for the prevention and/or treatment of Type 1 diabetes. .


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: What protects islet antibody positive T1D relatives who do not progress?
Funder: Juvenile Diabetes Research Foundation

Abstract: The ability to clinically delay or prevent T1D remains elusive but strategies targeting immune regulation have the greatest potential. Understanding the immunogenetic and regulatory mechanisms in those who have circulating islet autoantibodies, robust markers for future type 1 diabetes, but have not developed diabetes is likely to inform future therapeutic intervention. We have identified a cohort of first degree relatives with evidence of ongoing autoimmunity that has remained diabetes free (min 10 years and max 26 years) in whom “naturally occurring” regulation of the autoimmune response must be taking place. The cohort has been under long term follow up and we now propose a broad based approach to characterize immunogenetic and regulatory mechanisms in these individuals. Initially “slow progressors” will be tested for current glucose tolerance status. Markers of genetic susceptibility and islet autoantibodies characteristics will be studied in detail compared to individuals to progress rapidly to diabetes (fast progressors) and islet antibody negative relatives. Current CD4+, CD8+ and regulatory T cell function will be analyzed and compared with rapid progressors as well as those who have recently progressed to T1D and islet autoantibody negative relatives. When these baseline characteristics of slow progression have been established, an integrated model will be built to determine whether rate of progression can be predicted. We also plan longitudinal follow up of multiple islet autoantibody positive relatives, to examine the changing characteristics of progression in real time. These studies will shed light on an understudied population in T1D research and may ultimately identify specific characteristics of slow progressors. These will potentially inform strategies to delay the onset of type 1 diabetes in all at risk individuals. .


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Immunological markers of beta cell decline in new onset Type 1 diabetes
Funder: Juvenile Diabetes Research Foundation

Abstract: JDRF, TrialNet and other agencies have pioneered immune intervention trials in T1D that aim to establish optimal approaches (in terms of safety and efficacy) for the preservation of endogenous insulin secretion. The efficacy of clinical trials is usually evaluated by measurement of an integration of this metabolic triadŽ of stimulated C-peptide, HbA1c and insulin use. However, this does not provide significant insight into the immunologic pathways that have been impacted upon by the therapy. Although T1D clinical trials are frequently accompanied by immunologic studies, these are often treatment-centric (e.g., measuring B lymphocyte numbers in the anti-CD20 trial) and thus only reflect the effect of the single agent. Furthermore, the emphasis in clinical trial design is shifting towards new directions that may accelerate the translational pathway. These include the use of combinations; clinical studies aimed at gaining mechanistic insights rather than C-peptide end-points; and in the future, the stratification of patients for particular agent(s) based on phenotype as well as short-term studies in at-risk populations. For each of these initiatives, there is a compelling need for biomarkers that reflect the disease process as closely as possible. Our aim is to develop a consortium-based approach to study samples collected longitudinally and on which metabolic data are already available, and examine whether there are identifiable immune correlates of decline of beta-cell function. We will test the hypotheses that there are immunological markers detectable at diagnosis, the nature, level or phenotype of which reflect current, active insulin reserve (set-point); and/or that there are immunological markers that predict or correlate with the rate of decline of insulin reserve over the subsequent 3-24 months. These studies have the potential to identify immune correlates that can accelerate translational efforts in the setting of T1D cure and prevention.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE
Title: Microneedle arrays to deliver antigen specific immunotherapy
Funder: Juvenile Diabetes Research Foundation

Abstract: The results of recent antigen specific immunotherapy trials with oral insulin or subcutaneous GAD have been disappointing. In retrospect, insufficient attention was perhaps given to optimising the tolerogenic environment in which the antigen was administered. Current approaches to address this issue include expanding tolerogenic dendritic cells ex-vivo, engineering commensal bacteria to express antigen with tolerogenic molecules and coupling antigen to other agents. In preliminary experiments, we have shown that topical therapy of the skin can pre-condition antigen presenting cells at the site of treatment in the epidermis to acquire tolerogenic properties. However we also observed that topical treatment of the skin results in locally injected antigen reaching the spleen in 1-4 hours or less, suggesting that it is disseminated in fluid phase rather than presenting JDRF Strategic Research Agreement (SRA) - Microneedle arrays to deliver antigen specific immunotherapy - 2014 page 9 of 13to the immune system on the preconditioned cells at the site of treatment. Since this systemic dissemination effect occured both with hydration vehicle and steroid, it seems to be due to skin hydration and disruption rather than a direct effect of steroids. To address this, we propose to develop solid microneedles – very short steel structures (around 0.5 mm in length) that are coated with drug and penetrate only the very superficial layers of the skin. Treatment can be self administered, is virtually painless (as it is so superficial) , making it suitable for children as well as adults. We will develop a process to coat clinical grade microneedles to GMP standard with steroid and the proinsulin T cell target epitope proinsulin C19-A3 as a proof of concept. Following this a clinical study will be conducted in which combination coated microneedles are compared to peptide alone or inject peptide and topical steroid. The primary readout will be peptide specific IL-10 secreting cells measured by ELISPOT. To enhance our ability to detect responses, assays will be performed on draining (axillary) lymph node cells (obtained under ultrasound guidance) from the treated arm as well as on peripheral blood. We hope to demonstrate that the use of steroid and antigen co-coated microneedles represents a simple, low-cost, but potentially effective way of promoting antigen specific tolerance, leading to later phase 2 efficacy studies.


Research activity codes: 6.3 MEDICAL DEVICES;6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: MonoPepT1De trial
Funder: Juvenile Diabetes Research Foundation

Abstract: This protocol describes the use of the investigational medicinal product (IMP) known as PPI C19-A3 in a study of safety of administration in patients with new-onset Type 1 diabetes. PPI C19-A3 is a peptide of 18 amino acids comprising GSLQPLALEGSLQKRGIV (or using 3-letter designation: H-Gly-Ser-Leu-Gln-Pro-Leu-AlaLeu-Glu-Gly-Ser-Leu-Gln-Lys-Arg-Gly-Ile-Val-OH), the sequence of which is identical to the residues from position 19 in the C-peptide of proinsulin through to position 3 on the A-chain of the same molecule. The aim of the study is to examine the safety of i.d. administration of the naturally processed proinsulin peptide C19-A3 (PPI C19-A3) at a dose of 10μg every 14 days or every 28 days for a total of 12 and 6 doses, respectively, to patients with new-onset Type 1 diabetes. The objectives of this study are: • to examine the risk of C19-A3 administration in terms of general safety, induction of hypersensitivity and disease acceleration • to examine the effects of C19-A3 administration on appropriate biomarkers of disease (pro-inflammatory autoreactive T lymphocytes) and immune regulation (autoreactive regulatory T cells) JDRF Strategic Research Agreement (SRA) - MonoPepT1De trial Strategic Research Agreement (SRA) - Mark Peakman - 2014 page 8 of 13• to examine any benefits of 14-day as compared to 28-day dosing The study is a multi-centre, randomised, double-blind, placebo-controlled, 3-arm study of 10μg of PPI C19-A3 peptide administered every 14 or every 28 days for 24 weeks, with follow-up for 48 weeks. Adults with a diagnosis of Type 1 diabetes within the previous 100 days will be included in the study. Autoimmune diabetes will be confirmed by measurement of islet cell autoantibodies. Patients will be required to possess the HLA-DR4 (B1*0401) genotype.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Overnight closed loop in sub-optimally controlled type 1 diabetes under free living conditions (APCam11)
Funder: Juvenile Diabetes Research Foundation

Abstract: The main study objective is to determine whether overnight automated closed-loop glucose control combined with sensor augmented insulin pump therapy and threshold based pump interruption will improve overnight glucose control and reduce the burden of hypoglycemia compared to sensor augmented insulin pump therapy without the threshold based pump interruption feature. This is an open-label, multi-centre, multi-national, single-period, randomized, parallel group design study, involving a three-month period of home study during which overnight glucose levels will be controlled either by a closed-loop system combined with threshold based insulin pump interruption or by sensor augmented insulin pump therapy. It is expected that 90 subjects, aiming for 80 randomized subjects [40 youth (6 to 21 years), and 40 adults (22 years and older)], with type 1 diabetes will be recruited through pediatric and adult outpatient diabetes clinics in each of the investigation centers. Subjects who drop out within the first four weeks of the intervention may be replaced. Participants will all be on subcutaneous insulin pump therapy and will have proven competencies both in the use of the study insulin pump and the study continuous glucose monitoring device. Subjects will receive appropriate training in the safe use of closed-loop insulin delivery system and the threshold based pump interruption feature. Subjects will have regular contact with the study team during the home study phase including 24/7 telephone support. The primary outcome is the percentage of time overnight (midnight to 09:00 hours) with glucose levels between 3.9 and 8.0 mmol/l (70 to 144mg/dl), as recorded by unmodified continuous glucose monitoring. Secondary outcomes are the HbA1c, time spent with glucose levels above and below target, as recorded by continuous glucose monitoring, and other continuous glucose monitoring-based metrics. Safety evaluation comprises assessment of the frequency of severe hypoglycemic episodes.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Non-invasive glucose monitoring using high-frequency radio waves
Funder: Innovate UK

Abstract: We are developing the first accurate, non-invasive, wireless glucose monitoring system. The system consists of a wearable on-ear sensor, a mobile unit for receiving and displaying the glucose data, and a cloud-based software platform which interfaces with existing electronic health systems to store and provide data access to patients, carers or medical professionals. We will combine these systems onto a single IT and smartphone platform so that users have access to all the information they need to maintain effective control of their blood glucose levels and health care professionals can accurately monitor their treatment adherence. The main objectives of this system are to provide a pain-free, cheaper and more hygienic option to the current blood glucose monitors, while at the same time providing the user with the additional tools they need to effectively manage their condition.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE