- 2018Pump Priming
A role for hypothalamic hormones in the islet adaptation to pregnancyRecipient:Dr James BoweInstitution:King’s College LondonCity:LondonAmount:£17,782Description: During healthy pregnancy insulin sensitivity in the mother decreases and the insulin-secreting beta-cells in the islets of Langerhans release more insulin and increase in number to maintain normal blood glucose levels. Gestational diabetes mellitus (GDM) is a form of diabetes that occurs specifically during pregnancy and occurs when the maternal islets are unable to sufficiently compensate for the increased insulin resistance, though the mechanisms involved are currently poorly understood. Corticotropin releasing hormone (CRH) and growth hormone releasing hormone (GHRH) are two hormones that are primarily released from the hypothalamic area of the brain. They are responsible for controlling stress responses and growth respectively. Both hormones also have beneficial effects on the beta-cells, though the physiological reason for this is unknown. Levels of CRH and GHRH in the blood are low under most circumstances, but increase greatly during pregnancy due to release from the placenta. Thus, this project will investigate whether CRH and/or GHRH regulate beta-cell adaptation to pregnancy, and whether insufficient CRH or GHRH is linked to GDM.
- 2018Pump Priming
Bringing immunotherapy for type 1 diabetes into the clinic: new windows into the immune responseRecipient:Dr Danijela TatovicInstitution:Cardiff UniversityCity:CardiffAmount:£19,550Description: Type 1 diabetes (T1D) is caused when cells of the immune system called T-cells attack and destroy insulin producing cells in the pancreas. Monitoring of these pivotal immune cells is currently highly challenging as we cannot see what is happening in the pancreas. I have developed ways to monitor T-cell activity by studying organs called lymph nodes that act as ‘stations’on the transport network that T-cells use to travel around the body. These lymph nodes provide a window into what is happening in the pancreas during disease and allow monitoring of events during clinical trials. The technique I developed involves the use of a very fine needle that is guided using ultrasound. I now wish to use it to monitor the T-cells responsible for killing to insulin-producing cells using stateof-the-art technologies developed by my collaborators who are world leading experts in T-cells during T1D. This pump priming funding will allow me to establish important new collaborations aimed at monitoring T-cells during immunotherapy trials.
- 2018Pump Priming
Cx43 mediated regulation of the inflammasome, a therapeutic target in diabetic nephropathyRecipient:Dr Claire HillsInstitution:University of LincolnCity:LincolnAmount:£19,170Description: Cells lining the surface of the small tubes of the kidney work together to ensure that appropriate function is maintained. However, in the diabetic kidney, these cells become bathed in high levels of sugar and associated stress molecules that affect kidney cell behavior. We have previously demonstrated that high sugar reduces stickiness between kidney cells, an event that impairs the way in which cells talk to each other, and ultimately affects their ability to work efficiently. More importantly, our preliminary studies suggest, that in kidneys of people with diabetic nephropathy, there are altered levels of proteins responsible for transferring information between both cells and their surrounding environment. In the absence of appropriate data sharing, cells respond inappropriately to incoming danger changes and ultimately kidney function is impaired. Our proposal aims to understand the mechanisms which link inappropriate cell conversation to the damage that occurs in the diabetic kidney. Importantly, in collaboration with our clinical colleagues, we will demonstrate the ability of a new therapeutic to negate these effects.
- 2018Pump Priming
Defining heterogeneity of clinically diagnosed adult-onset type 1 diabetes using genetic and islet autoantibodiesRecipient:Dr Kashyap PatelInstitution:University of Exeter Medical SchoolCity:ExeterAmount:£18,581Description: Half of all type 1 diabetes develops in adulthood. Half of these patients are misdiagnosed and therefore potentially treated incorrectly. This is due to both lack of tools to confirm type 1 diabetes at diagnosis and overlapping features with other subtypes of diabetes (type 2 diabetes and monogenic diabetes, a rare familial diabetes due to mutation in a single gene). This study will analyse whether the combination of currently used blood tests (islet autoantibodies) and a new DNA–based tool (type 1 diabetes genetic risk score, T1D-GRS) can reduce misdiagnosis. We will measure the efficacy of these tools in 700 people with clinically diagnosed adult-onset type 1 diabetes (age at diagnosis 20-80 years). Genetic tests will be used to identify misdiagnosed monogenic diabetes. This study will provide a framework for the accurate diagnosis of adult-onset T1D in routine clinical practice. The study will also be the first to provide an estimate of misdiagnosed monogenic diabetes, resulting in patients getting the correct treatment and better care.
- 2018The Professor David Matthews Non-Clinical Fellowship
Improving islet transplantation outcomes by harnessing the mesenchymal stromal cell secretome to target the donor islet graft and host environmentRecipient:Dr Chloe RackhamInstitution:King’s College LondonCity:LondonAmount:£194,934Description: This research aims to define the mechanisms though which Mesenchymal Stromal Cells (MSCs) or the biologically active substances that they produce should be used to improve the efficiency of clinical islet transplantation. Our experiments have shown that MSCs produce Annexin A1 (ANXA1) and that ANXA1 partially mimics the beneficial effects of using MSCs. We aim to define a 'cocktail' of therapeutic factors produced by MSCs, that can be used instead of the MSCs, to fully reproduce the beneficial effects of MSCs in transplantation protocols. Defining MSC-derived biotherapeutics will allow simple modifications to clinical transplantation, that will help to overcome some of the safety concerns of using MSCs directly and allow safe and reproducible modifications to be carried out. The proposed work will help design and start a clinical trial within the next five years. Through improving the efficiency of the transplant procedure, clinical islet transplantation can be offered as a therapeutic option to the greatest possible number of patients with Type 1 Diabetes and improve outcomes for individual transplant recipients.