Funded Research

In type 1 diabetes (T1D) the cells within the pancreas, which produce the hormone insulin, are destroyed by the immune system. Injecting insulin is the main form of treatment for T1D patients but in some patients giving insulin does not control their diabetes and they can go on to develop severe problems of the eyes, kidneys, nerves, brain and heart. In these patients, a transplant of the pancreas or the cells from a pancreas is currently the only treatment that can restore the patient’s own ability to produce insulin, as well as improving diabetes related complications. At present 85% of pancreas transplant patients regain normal pancreas function one year after transplantation, enabling them to discontinue insulin use. Transplanted pancreas function can, however, decrease over time and in some patients stop completely, with only 68% of transplant patients having a functional pancreas after five years. Decreased or lack of transplanted pancreas function means a return to insulin and potentially further worsening of other diabetic complications. Currently we cannot predict when the transplanted pancreas will start to fail. I want to test the genetic material obtained from both pancreas transplant donors and recipients, from all pancreas transplant centres across Europe and America, to investigate naturally occurring variations within genes influencing transplant rejection and pancreas development/function to help us try to predict when the transplanted pancreas is likely to fail so that we can administer medicines that might extend the pancreas’ lifespan and the benefits to patients of having a functioning pancreas for as long as possible.

RNA has long been seen as an intermediate between DNA of the genome and functional proteins, however only around 2% of the different RNA molecules in the cell perform this role. Many of the remaining non-protein-coding RNAs (ncRNA) play a previously underappreciated role in regulating the specific pattern in which the protein-coding genes are turned on and off. This is critical for determining the type of cell produced, and in the case of the β-cell, how well it can perform its role of glucose-regulated insulin secretion. The failure of β-cell function is the critical step in the development of type 2 diabetes (T2D). Understanding the mechanisms which maintain that function provide the opportunity both to help boost β-cell function in patients with T2D, and increase the efficiency and efficacy of producing β-cells from stem cells in vitro for treating diabetes through transplantation. I aim to identify how ncRNAs regulate β-cell function in three areas. Firstly, whether novel ncRNAs keep a group of genes which would interfere with β-cell function specifically turned off in these cells. Secondly, how a ncRNA I have already identified regulates the levels of Pdx1 (a gene known to regulate β-cell function). This may partly control the process in which another type of cell in pancreatic islets can turn into new β-cells, which could help block the progression of diabetes. Finally, whether previously unidentified lncRNAs could explain why mutations in humans which are not close to known genes affect susceptibility to T2D.