Grant: CIHR Fellowship

Type 1 diabetes is caused by the destruction of insulin-secreting beta-cells in the pancreatic islets. Beta-cell death also hinders efforts to treat diabetes through islet transplantation. Since we do not adequately understand the processes that govern beta-cell death, strategies have not yet been developed to stop or prevent diabetes. Although islet transplantation was initially a promising therapy for type 1 diabetes, the inability to prevent beta-cell death means that we have not yet achieved the degree of success that was originally proposed. Insulin has recently been identified as a critical pro-survival factor for beta-cells, but the mechanisms that lead to the beneficial of insulin are unknown. In my post-doctoral fellowship, I wish to undertake new studies aimed at determining the mechanisms by which insulin acts on the beta-cell. There is now strong evidence that insulin can activate a protein called Raf-1 kinase, and this protein has been shown to have an important role in regulating cell death. I intend to test the hypothesis that Raf-1 is essential for beta-cell survival using a combination of state-of-the-art molecular and imaging techniques on mouse and human pancreatic islets, as well as islets from mice that lack the Raf-1 gene in their beta-cells. The results of these studies will hopefully give a better understanding of the mechanisms of beta-cell death, and they may lead to novel therapeutic strategies for preventing beta-cell destruction in type 1 diabetics and their at-risk relatives. Furthermore, an understanding of the pathways involved in beta-cell survival may also lead to new methods to increase the survival of beta-cells after islet transplantation, thereby increasing the effectiveness of this treatment for future patients.