application) Transplantation of islets of Langerhans into the diabetic patient possesses the potential to reverse long-term hyperglycemia through tightly regulated physiological changes of serum insulin levels. To date long-term success of islet transplants has been limited. The reasons for this are not completely understood but it has been hypothesized that long-term failure of the transplanted graft to maintain normoglycemia results from a loss in B-cell mass and/or function over time. The overall goal of the proposed research is to develop capabilities for in vivo evaluation of pancreatic islet mass and function at various temporal stages following transplantation. The research strategy will include development of transgenic mice, producing pancreatic islets with """"""""imagable"""""""" insulin-secreting B-cells, characterization of these islets with regards to B-cell mass, function and apoptosis and subsequent transplantation of transgenic islets into nude mice, allowing posttransplantation studies of graft mass and function with time. Since the grafts are vascularized and the experiments will be performed with the kidney connected to the circulatory system of the mouse, this will also provide the first steps towards evaluation of B-cell signal-transduction under in vivo conditions. More specifically we will: 1. Develop methodologies for in vivo imaging of B-cell mass in transplanted islets of Langerhans; 2. Develop and apply novel methodologies for in vivo monitoring of B-cell function within the islet graft; 3. Develop and apply methods to allow in vivo detection of B-cell apoptosis within the islet graft. At the end of this grant period we should be in the position to address the molecular mechanisms resulting in B-cell incapacitation following transplantation of functional islets into diabetic recipients and to possess the necessary methodologies to investigate signal-transduction in pancreatic B-cells under in vivo conditions and in situ.
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