Description of ProjectBeta cells, a type of cell residing in the pancreas, are responsible for the production of insulin. Insulin is a hormone that assists in the regulation and utilization of glucose—the basic storage unit of energy in all vertebrates. Type 1 diabetes is characterized by a reduction in beta cell number and insufficient insulin production and results in hyperglycemia (high blood sugar) and hypoglycemia (low blood sugar). Severe hypoglycemia can result in organ failure, coma or death. Prolonged hyperglycemia can result in blindness, amputations, kidney failure and organ damage.Critical to the treatment of type 1 diabetes is the restoration of appropriate beta cell number and function. In patients with type 1 diabetes, beta cell populations remain depressed or absent and do not naturally regenerate themselves. Stem cell therapy presents an attractive approach to generating beta cells for replacement and treatment of type 1 diabetes. Stem cells may be coaxed into forming many different cell types in the body including beta cells. The signals that induce stem cells to change into a specific cell type are beginning to be understood. The majority of signals identified so far are proteins and are expensive and difficult to produce and purify. Additionally, the use of these proteins is inefficient and results in a small number of beta cells.A recently emerging approach that utilizes less expensive small molecules, or synthetic chemical compounds, has shown promise mimicking and replacing expensive protein-based signals. Fortuitously, these small molecules also result in more efficient transformations with larger numbers of cells converting to the desired cell type.Recent progress in applying this approach to the generation of beta cells from stem cells has resulted in the identification of small molecules that direct stem cells through two intermediate steps along the pathway to beta cells; however, there are no known small molecules that can direct these cells along the final two steps of this pathway to beta cells.Herein I propose a high throughput screen of thousands of potential drug candidates to identify compounds that can induce the final two steps of the differentiation pathway to pancreatic beta cells. The expectation is that the identification and subsequent mechanistic elucidation of small molecules that modulate this process will allow for new insights into the biology behind the generation of beta cells. The development of high efficiency strategies for chemical differentiation would lay the groundwork for potential beta cell replacement therapies to treat type 1 diabetes.
|Effective start/end date||9/1/11 → 8/31/14|
- Juvenile Diabetes Research Foundation United States of America: $139,944.00