Recent clinical trials of islet transplantation for the treatment of patients with Type 1 diabetes have shown that biological replacement of insulin producing tissue is a viable therapeutic option. Enthusiasm has been re-ignited in the scientific community by the successful results at Edmonton and at other institutions, including our own. These very promising results have also highlighted the urgent need for optimizing the use of available human islets for transplantation. In fact, it was generally required to use at least two donor pancreata to treat each recipient, and this contributes to the sizeable gap between human pancreata availability and number of patients that could potentially benefit from islet transplantation. Selected approaches to tackle and resolve this problem represent the major focus of this grant. First, strategies aimed at increasing human islet availability via the use of better organ preservation will be studied. Second, strategies aimed at preventing islet cell death during isolation and in vitro culture, as well as in the peri-transplant period, will be analyzed to ameliorate the donor-recipient ratio necessary for successful islet transplantation. It is, therefore, the central hypothesis of this grant, that implementation of strategies to improve availability, viability, and functional performance of human islet preparations will result in an increased number of successful clinical islet transplants. In this grant, we propose the following specific aims: 1) to improve the availability and quality of human pancreata utilized for islet isolation by reducing islet loss/dysfunction that occurs as a consequence of pancreas procurement/preservation; 2) to improve in vitro islet culture conditions, to maximize recovery of viable, functional human islets for transplant applications; 3) to prevent islet damage/death in the peri-transplant period by inducing islet cell cytoprotection and preventing apoptosis. Strategies to study these major aims will be based on relevant end-points, such as analysis of islet yield after isolation, following novel pancreas procurement strategies, analysis of islet cell apoptosis and necrosis in novel culture conditions, and analysis of in vitro and in vivo islet function by the use of informative models of glucose-stimulated insulin secretion and analysis of functional potency in immunodeficient rodents. Strategies to improve islet availability, viability, and functional potency will include of hypoxia during pancreas preservation, modifications of culture that allow the prevention of spontaneous death and/or functional impairment, and manipulation of islets that induce protection against noxious stimuli, such as pro inflammatory cytokines and nitric oxide, likely to be responsible for substantial islet loss in the peri-transplant period. Achievement of the proposed goals will allow us to extend islet transplantation as a therapeutic option to a large cohort of patients with Type 1 diabetes
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