Understanding Beta-cell survival and intracellular responses to its environment are critical for the creation of improved therapy for the growing number of Type 2 diabetic individuals. Mechanisms underlying regenerative capacity, function, and cell-cycle of pancreatic Beta-cells are for the most part unknown and likely mediated by the extracellular signaling of nutrients and growth factors. The Ras signaling pathway encodes proteins that activate in an intracellular signaling network controlling differentiation, apoptosis, proliferation, and cell survival, although the coordination of these processes is not understood in the Beta-cell. For this fellowship, I will characterize Ras-pathway expression patterns coupled with Beta-cell function and survival data of tissue-culture B-cell lines and mice islets subjected to various nutrient, hormonal, and Ras-inhibitory conditions. In addition to observing Ras expression and downstream effects from extracellular manipulation, I will use these same Beta-cell tissue culture cell lines and mice backgrounds and genetically impose upregulation or downregulation in one of the Ras downstream branches. I hypothesize that how the downstream branches of the Ras signaling pathway interact depends on a cellular goal of whether or not to survive, as influenced by extracellular signaling. Again, data from these experiments will be from proliferation, apoptosis, and expression studies along with Beta-cell insulin production. Which goals and approaches the Beta-cell chooses in response to nutrient and hormonal signaling will provide insight to how to best understand and treat the progressive Beta-cell failure of Type 2 diabetes.
