NIHRDataInsights/HRCSData huggingface dataset:
Title: Omega-1, a novel immunomodulator with potential to prevent Type 1 diabetes?
Funder: Medical Research Council

Abstract: Omega-1 is a glycoprotein produced by the helminth Schistosoma mansoni. We find that this glycoprotein can induce Foxp3 expression, a marker of regulatory T cells, in na?ve CD4+T cells from NOD mice. As our previous studies have shown that extracts containing this glycoprotein can prevent diabetes onset in the NOD mouse model of T1D we propose to determine whether Omega-1 induces functional regulatory T cell activity in T cells from both NOD mice and T cells from diabetic patients. We will furthermore characterise the signalling pathways involved when Omega-1 interacts with the immune system. We will additionally determine whether Omega-1 is able to prevent diabetes onset in NOD mice.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Defining novel genetic mechanisms of congenital hyperinsulinism
Funder: Medical Research Council

Abstract: Congenital hyperinsulinism (CHI) is a cause of severe hypoglycaemia in the childhood period and a major cause of hypoglycaemic brain injury. The genetic basis of CHI involves defects in key genes (ABCC8, KCNJ11, GLUD1, GCK, HNF4A, SLC16A1, and HADH) involved in regulating insulin secretion from pancreatic beta-cells. CHI is an extremely heterogeneous condition where the genetic aetiology is known in only about 40% of patients suggesting other novel genetic mechanisms Our research focuses on understanding the genetic mechanisms of CHI that lead to dysregulated insulin secretion. We have established the largest (800) cohort of patients with CHI in the world that have been systemically phenotyped and genotyped and will form the backbone of our proposed research. We have generated significant preliminary data illustrating novel mechanisms of insulin secretion. Understanding the mechanisms that regulate insulin secretion will have important implications for beta-cell physiology and other common conditions such as diabetes mellitus. Even more importantly unrevealing these mechanisms will help in patient management and allow appropriate genetic counseling


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Using Whole Exome Sequencing (WES) to identify genes underlying unexplained Maturity Onset Diabetes of the Young (MODY-X)
Funder: Medical Research Council

Abstract: Monogenic forms of early-onset non-autoimmune diabetes typically occur before the age of twenty and are characterized by primary pancreatic beta-cell dysfunction, generally resulting in severe defects in insulin secretion. This is called Maturity-Onset Diabetes of the Young, or MODY, and where the underlying gene defect is unknown it is referred to as MODY-X. Currently, MODY prevalence is estimated to be 1-2% of all European T2D cases. A recent estimate of the population prevalence in the UK reported a minimum prevalence of 108 cases per million, giving an estimated 6500 MODY patients in the UK alone. In spite of many successes, in the majority of cases the underlying genetic defect remains unknown. With the ability to sequence all the coding regions in a genome, whole exome sequencing (WES), in a timely and efficient manner, it is now possible to explore characterisation of MODY of unknown cause (MODY-X). The current proposal utilises WES of four subjects form each of six multi-generational MODY-X) families followed by identification of strong candidate SNPs by using a filtering system. Initial filtering will be based on bioinformatics information, prioritising SNPs that are missense, nonsense or frameshift. Predictions of possible effects on protein structure and function will also be examined. Segregation analysis of the remaining candidate variants will then be carried out to confirm clear transmission of the variant together with MODY. Absence of the variant from unaffected individuals will be confirmed in a set of 760 unrelated French Caucasian adults. Genes containing variants that pass all criteria will then be investigated in a further 15-20 MODY-X families for the presence of the novel variant, or other variants, which may be responsible for their MODY-X. Novel variants will also be examined for their presence in a set of ~200 type 2 diabetes patients with evidence of monogenic transmission in their family. Overall, this strategy will lead to the identification of multiple MODY-X gene variants, which may lead to the identification of additional genes that are involved in MODY and possibly have wider implications for our current understanding of the genetics of type 2 diabetes.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Over three years for the development and evaluation of metal-based therapeutic strategies for Lysosomal Storage Disease
Funder: Action Medical Research

Abstract: Background_x000D_ Lysosomal storage diseases are a group of over 60 genetic disorders that prevent cells of the body from removing waste materials. One such disease is called Niemann-Pick type C (NPC) and affects about 100 children in the UK at any given time. In NPC disease, a gene mutation means that lysosomes, which are the waste disposal and recycling centres of the cell, are not working properly and unwanted fatty molecules build up causing progressive nerve damage. Symptoms of NPC include problems with swallowing, gradual loss of speech and movement, learning difficulties and dementia. There is currently only one treatment for NPC that slows the course of the disease, so additional treatments are urgently needed. In trying to understand more about what goes wrong in NPC and related conditions, these researchers have focussed on the role of metals. It is known that very low levels of metals such as iron, copper and zinc are essential for the cells in our body to work normally. This team has been looking to see whether changes in the way metal levels are controlled by lysosomes can contribute to the development of NPC and related diseases. Early work has shown that iron levels are lower and copper levels are higher than normal. Correcting these abnormalities in a mouse model of NPC led to fewer symptoms in the mice. _x000D_The research project_x000D_ The researchers now plan to study the role of metals in lysosomal storage diseases in more detail and to evaluate metal-based treatments for NPC and two related, lysosomal storage diseases called the gangliosidoses. If the team are able to gain a clearer understanding of exactly how metals fit into the disease process, this will allow them to target simple, appropriate metal-based treatments. For example, low iron levels could be treated by iron supplementation. Raised copper levels could be lowered by giving medicines to reduce absorption of copper from the digestive tract. As these treatments are already licensed to treat other diseases, for example, iron supplements to treat anaemia, this research could quickly translate into much needed treatments for children with these rare and disabling conditions.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Over three years: Evaluating stem cell gene therapy for treating the brain in Mucopolysaccharidosis IIIB
Funder: Action Medical Research

Abstract: Background_x000D_ Sanfilippo IIIB, also known as Mucopolysaccharidosis IIIB, is a rare, inherited lysosomal storage disease. Lysosomes are the recycling centres of the cell, responsible for breaking down waste materials. In Sanfilippo IIIB, a gene mutation results in deficiency of an enzyme needed to break down large sugar molecules. Without this enzyme, sugars accumulate in the brain and cause severe neurological problems Symptoms first appear in children between two and five years of age and include disturbed sleep, severe behavioural and learning difficulties and progressive loss of movement. There is no treatment for Sanfilippo IIIB and sadly, life expectancy is less than 20 to 30 years. Although very rare in the UK (only a few cases a year), it is more common in southern Mediterranean countries and some of these children are referred to UK clinics for diagnosis and advice. Enzyme deficiency diseases can sometimes be treated by injecting the missing enzyme into the patient's bloodstream but this does not work in Sanfilippo IIIB because the enzyme is unable to get to the brain where it is needed. Another approach is to use bone marrow transplantation. Bone marrow stem cells from a healthy donor are injected into the patient, some pass into the brain and start producing the missing enzyme. However, this has so far been unsuccessful in Sanfilippo IIIB as not enough enzyme is produced by the stem cells._x000D_ The research project_x000D_ The researchers aim to increase the amount of enzyme produced by stem cells after transplant using gene therapy. Rather than using donor stem cells, they want to develop a technique which would allow a patient's own stem cells to be modified by gene therapy and then transplanted back into the patient. This is considerably safer than using donor stem cells which the body may recognise as 'foreign' and try to reject. The team hope that this research will lead to a safe and effective treatment for this devastating disease and that the experience gained will be of value in treating other similar conditions.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: METABOLIC AND ENDOCRINE
Title: Frequency of screening for diabetic retinopathy - Risk stratification and cost-effectiveness study
Funder: Division for Social Care and Health Research (Wales)

Abstract: Diabetic Retinopathy (dr) (damage to blood vessels at the back of the eye) is a major complication of diabetes and a leading cause of blindness in the working age population. Screening for dr ensures early detection when treatment is most effective in preventing loss of vision. In Wales, dr screening is conducted by the Diabetic Retinopathy Screening Service for Wales, and current recommendations state screening should be carried out yearly for those with diabetes. The number of people diagnosed with diabetes is increasing and the current level of resources will be unable to accommodate future demand. All people with diabetes have eye photographs and basic information (age, sex, type and duration of diabetes) taken at their screening visits. Information on other risk factors (e.g. glucose control, weight, blood pressure and cholesterol) will be obtained from GPs. We will use modelling and statistical techniques to predict those who will or will not develop diabetic retinopathy. We will then devise, test and refine procedures to identify those individuals who require frequent and those who require less frequent screening based on risk. The objective is to develop and validate a safe and more cost- effective programme of screening for dr for people with diabetes.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE
Title: Development and validation of an LC-MS/MS method for the measurement of IGF-1.
Funder: Department of Health (England)

Abstract: Insulin-like growth factor 1 (IGF-1) is used in the diagnosis and monitoring of growth hormone excess and deficiency. IGF-1 is most often measured by automated immunoassay, which uses antibodies to quantify IGF-1 in a blood sample. These assays are unsatisfactory, as the results can vary depending on the manufacturer of the immunoassay, meaning that different results may be produced depending on where you get your samples analysed. We decided to develop a method for measuring IGF-1 using mass spectrometry, which separates molecules according to their weight, to produce a ‘gold standard’ test which could be used by immunoassay manufacturers to standardise their methods. We decided to digest IGF-1 using trypsin as IGF-1 is too big to measure using mass spectrometry. We optimised the method and chose four different portions of the digested molecule to measure. The results appeared promising but we weren’t able to detect low enough concentrations of IGF-1 for the assay to be clinically useful, even after further optimisation. A different approach was then chosen, looking at the full IGF-1 molecule with multiple positive charges to enable measurement by mass spectrometry. We were able to measure IGF-1 using this method in aqueous samples but encountered problems when trying to analyse blood samples as there was a high background signal from these samples which made it very difficult to distinguish the IGF-1 signal from the background. Attempts were made to clean-up these samples prior to analysis but the methods we used did not work. Further work is required to optimise sample clean up and enable measurement of low concentrations of IGF-1 in patient samples.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: METABOLIC AND ENDOCRINE
Title: Short term use of a glucose meter to enhance dietary education as part of an intervention for type 2 diabetes prevention among people with impaired glucose regulation
Funder: Chief Scientist Office, Scotland

Abstract: We wish to work with people who have been diagnosed with impaired glucose regulation (who have blood sugars higher than normal but not high enough to be diagnosed with diabetes) to encourage them to make changes to their lifestyle. We are wondering whether a short 4-week period of blood sugar monitoring using a glucose meter would help them to see/experience at first-hand the effects of different foods and drink on the body. This idea came from a lay person with diabetes, but we don’t know whether it would be considered acceptable to people who have not yet developed diabetes, and whether they would make use of the opportunity. We will therefore test this by giving a glucose meter to 20 people with impaired glucose regulation for 4 weeks and exploring their experiences afterwards.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: METABOLIC AND ENDOCRINE
Title: Finalising the mode and timing of delivery of an intervention to address illness perceptions of diabetes among women with previous gestational diabetes
Funder: Chief Scientist Office, Scotland

Abstract: Women who had diabetes during pregnancy (gestational diabetes; GDM) have a high chance of developing type 2 diabetes in later life. There is very little aftercare post-pregnancy and this reinforces their perception that GDM is not an important diagnosis. We question whether home visits from health visitors and/or attendance for cervical cancer screening could be used for discussions about diabetes risk to address this problem. In this project we will consult with primary care colleagues as to how this could work. We will also explore diabetes risk with around fifteen women with previous GDM at a routine /cervical cancer screening visit, and explore their views/experiences afterwards.


Research activity codes: 5.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: METABOLIC AND ENDOCRINE
Title: Developing a Scottish type 2 diabetes policy model and piloting a web based decision aid "Dashboard".
Funder: Chief Scientist Office, Scotland

Abstract: Approximately 1 in 20 people in Scotland have diabetes: a major cause of blindness, kidney failure, heart attacks, stroke and lower limb amputation. As in many other countries, the numbers of people with type 2 diabetes is rapidly increasing. This will lead to an increase in diabetes-related complications, affecting patients’ length and quality of life. This research will exploit Scotland’s excellent administrative and clinical databases to develop a diabetes policy model to help decision making about how to spend money in the health service. It is very important to understand the implications of new diabetes treatments on long-term health outcomes and costs. Our model will inform how best to use limited resources to achieve the best population health gains. The development of a web-based “dashboard” will enable policymakers to interact with the model easily and in a timely manner to help their decision-making. We will also pilot the use of this tool for use by clinicians and patients.


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS
Health categories: METABOLIC AND ENDOCRINE
Title: Generation of stem-cell based endocrine tumour models - tools for the development of personalised therapies
Funder: Chief Scientist Office, Scotland

Abstract: Rapid advances in DNA sequencing technologies have provided unprecedented insights into the genetic basis of disease. These include both the accelerated discovery of genes responsible for hereditary disorders, as well as the acquired changes in DNA sequence that result in common diseases such as cancer. These advances afford many potential opportunities, not least the advent of novel treatments and personalised therapies tailored to specific genetic defects. However, in many instances, this improved genetic understanding has not translated into a clinical benefit for patients, and one of the major barriers to progress has been a lack of relevant laboratory model systems to investigate how specific gene mutations affect the cellular environment and contribute to disease pathogenesis. The apparent failure to translate genetic advance into clinical benefit is evident in the field on endocrine oncology. For example, whilst studies over the past decade have provided increasingly rich genetic characterization of a large number of endocrine tumours occurring in both hereditary and sporadic (i.e. without a family history) settings, little progress has been made in developing new treatments and improving patient outcomes. My research group, funded by the Senior Clinical Academic Fellowship, is focused on investigating how such inherited (i.e. ‘germline’) and acquired (i.e. ‘somatic’) changes in DNA sequence contribute to endocrine tumour formation. To achieve this, we are exploiting recent advances in stem cell biology and gene-editing to establish novel pre-clinical model systems, with the aim of not only understanding early events in tumour formation, but also of establishing a resource for early drug-discovery. The use of human pluripotent stem cells (hPSCs) offers huge potential for disease modelling, highlighted by their ‘normal’ genetic make-up, unlimited capacity for self-renewal and unique ability to undergo differentiation into disease-relevant cell types (e.g. endocrine cells). In addition, when coupled with gene-editing methods, hPSCs offer an unrivalled exploration of cell-type and context-specific gene function, features likely to be critical to understanding disease pathogenesis. In summary, the overarching aim of this research program is to translate the recent advances in endocrine tumour genetics into improved molecular understanding and downstream therapeutic benefit.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE
Title: Regulation of brown adipose tissue and cold-induced thermogenesis in humans
Funder: Chief Scientist Office, Scotland

Abstract: Approximately two-thirds of adults are now at least overweight with a quarter of the population classed as obese. Obesity causes diseases such as type 2 diabetes, high blood pressure, high cholesterol and increases the risk of developing heart disease. Currently there are very few medications available to aid weight loss and new agents are required to tackle this obesity epidemic. While obesity is characterised by having too much fat or adipose tissue, there is another type of fat in our body called brown adipose tissue or BAT. This tissue’s main function is to generate heat to keep our bodies warm when we’re in a cold environment. Interestingly, people who are obese have less BAT than lean individuals. In rodents, activating BAT causes weight loss and lowers blood glucose and lipid levels. Therefore, activating BAT in humans is an exciting new strategy to treat obesity. However, we have only limited knowledge of how human BAT activation is controlled. My research group, funded by the Senior Clinical Academic Fellowship, focuses on identifying the pathways which control how our bodies activate brown adipose tissue to increase energy expenditure. We do this primarily in two ways, firstly by obtaining human brown fat cells from patients undergoing surgery and testing how these cells are activated. Secondly, we perform research studies in humans to see if we can increase their energy expenditure by activating their BAT. We hope that, by improving our understanding of how human BAT is activated, we can identify new therapeutic targets which we can subsequently manipulate to safely activate BAT and increase energy expenditure as a novel treatment for obesity and associated metabolic diseases.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE
Title: Preclinical testing of novel allogenic GMP grade mesenchymal stromal cells to promote the long term engraftment and function of human islets
Funder: Chief Scientist Office, Scotland

Abstract: Islet transplantation is effective in stabilising blood glucose control in Type 1 diabetes, but people rarely come off insulin and over time islet transplant function decreases. Two to three donor pancreata are required per person as in the process of islet transplantation into the liver, most islets are lost because of immune rejection, inflammation and a failure to “engraft” that is form blood vessels with the liver. Mesenchymal stromal cells (MSCs) decrease inflammation, promote blood vessel formation and decrease the rejection of transplanted organs. We have shown that when islets are co-transplanted with human-MSCs into the kidney in a mouse model without an immune system, there is improved engraftment of islets, tighter glucose control for a longer period of time and improved graft vascularity. Our aim is now to emulate the human situation and transplant islets in a mouse model with an immune system using the clinically relevant route of transplantation into the liver to determine 1) the effectiveness of islet+MSCs on controlling glucose 2) the way in which islet function is improved and 3) the safety of these MSCs. If successful this would lead to clinical trials with these human MSCs that are already approved for use in man.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: METABOLIC AND ENDOCRINE