- 2016The Professor David Matthews Non-Clinical Fellowship
Epigenetic changes in multi-generation type 1 diabetes familiesRecipient:Dr Jody YeInstitution:University of BristolCity:BristolAmount:£179,774.00Description: Type 1 diabetes is caused when the immune system makes a mistake and destroys the insulin-secreting beta cells in the pancreas. We know that genes play an important role in causing the condition but factors in our environment such as viral infections, pre-natal environment, and early nutrition are also thought to be important. Over recent decades, the incidence of type 1 diabetes has increased rapidly (~3% annually especially in children under 5 years of age). In addition, more people with less type 1 diabetes associated genes develop the condition today compared with previous generations. This suggests the increasing importance of environmental effects in type 1 diabetes. Unlike genes that are usually inherited unchanged from parents, DNA itself can be chemically modified, a phenomenon called DNA methylation. This process has been shown to be changed by environmental exposures and can be different in one individual to another. My collaborator, Professor Yaron Tomer and his team at Albert Einstein College of Medicine in New York has already shown that methylation differences can be found in identical twins where one twin was affected by type 1 diabetes while the other was not. In my three-year fellowship, I will travel to Professor Tomer’s laboratory to study multi-generation type 1 diabetes families from the Bart’s Oxford (BOX) family study of type 1 diabetes which has been running for over 30 years. I am going to investigate whether DNA methylation has changed in children with type 1 diabetes compared with their parents and grandparents. This study will allow us to find out whether the changing environment over time is associated with the increasing incidence of diabetes by modifying our DNA. We hope that this research will identify new markers that can be used in clinical trials to more accurately assign disease risk. In addition, we will dissect the underlying molecular mechanisms to uncover why environmental exposures trigger changes to the immune system leading to beta cell death. In the longer term, if we can understand why type 1 diabetes is becoming more common we may be able to intervene to delay or prevent the condition.
- 2016Pump Priming
The mechanisms linking glucose sensing to autophagic flux in pancreatic beta-cellsRecipient:Dr Catherine ArdenInstitution:Newcastle UniversityCity:NewcastleAmount:£19,715Description: Type 2 diabetes (T2DM) occurs when the insulin-releasing beta-cells of the pancreas fail to secrete sufficient insulin, a consequence of decreased insulin release and decreased cell number. The purpose of the proposed work is to explore a role for autophagy in the regulation of beta-cell number. Autophagy is a recycling system that uses damaged cell components to provide energy in response to changes in fuel availability, and can either act to promote cell survival or cell death. The aim of the proposed study is to explore how beta-cells regulate autophagy in response to changes in glucose concentration. We will explore how beta-cells alter their cell recycling mechanism in response to both acute and chronic changes in glucose levels and investigate the cellular mechanisms involved. The data generated by this pilot study will provide the basis for future large scale grant applications investigating the molecular links between glucose-sensing and autophagy in beta-cells and how these pathways impact on beta-cell number in T2DM
- 2016Pump Priming
Understanding the relationship between lipid droplet pattern and mitochondrial function and morphology in human primary hepatocytesRecipient:Professor Leanne HodsonInstitution:OCDEMCity:OxfordAmount:£19,382Description: More people with type 2 diabetes have fatty liver disease than people without diabetes. Liver fat accumulation (steatosis) consists of either a large number of small (microsteatosis) or one large (macrosteatosis) fat (lipid) droplet within liver cells (hepatocytes). Large lipid droplets are thought to interfere with the part of the cell that produces energy (mitochondria) so that they don’t work efficiently. We will investigate the relationship between lipid droplets and mitochondrial function in human liver cells. Liver tissue will be obtained from patients undergoing surgery and from this hepatocytes will be isolated. We will then measure the size and number of the lipid droplets and their localisation to mitochondria, using a state-of-the-art automated imaging machine. We will also assess the health and function of the mitochondria by determining their ability to produce energy. This work will help us to understand the relationship between fat in the liver and mitochondrial function and also provide information about pathways that new drugs could be developed for to help to keep the liver healthy
- 2015Pump Priming
Bile acid metabolism and recycling in improving type 2 diabetes resolution after bariatric surgeryRecipient:Dr Jia LiInstitution:Imperial College LondonCity:LondonAmount:£19,672Description: Roux-en-Y gastric bypass (RYBG) surgery is effective in treating morbid obesity and it carries a so-called ‘magic effect’, such as remission of type 2 diabetes (T2D). Recently, increasing scientific evidence suggest that bile acids, a group of molecules regulating lipid metabolism and secretion of gut hormone and insulin, play an essential role in T2D remission. The aim of my study is to determine what types of bile acids are re-absorbed and how they link to T2D remission after RYGB. Gut contents, portal vein blood through which the re-absorbed bile acids come back to the liver and the liver will be collected from fatty and diabetic rats, either undergone RYGB surgery,sham operation or caloric restriction. Bile acid composition of all samples will be measured using mass spectrometry. These resulting findings will lead to discoveries of new treatment and direct us towards a safer and non-invasive way of treating diabetes.
- 2015Pump Priming
Does reorganisation of the Extracellular Matrix promote glucose induced fibrosis in Diabetic Nephropathy?Recipient:Dr Claire HillsInstitution:University of LincolnCity:LincolnAmount:£18,000Description: In the diabetic kidney, a build up of fibrotic material in the proximal region of the nephron, in part, mediates both structural and functional damage culminating in loss of both cell integrity and function. Damage occurs when cells fail to respond as they should, and thus start behaving more characteristic of cells of another tissue type. In doing so, cells lose their ability to synchronize their activity with neighbouring cells. They become less able to directly adhere to surrounding cells and to the extracellular matrix; a skeleton, which surrounds and supports the cell. Loss of these interactions results in failure of transmission of cell survival signals. To date we know little of how high levels of glucose disrupts, both cell structure and function in the proximal nephron. The current proposal will utilize healthy and diseased proximal tubule cells to establish how high glucose and downstream fibrotic Transforming Growth Factor Beta both regulate and disrupt cell-cell and cell-ECM interactions. The aim of these studies is to identify a future therapeutic target for alleviating renal fibrosis in diabetes.