Gene Transfer and Revascularization of Transplanted Isl*

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): Pancreatic islet transplantation holds great promise for the treatment of type I diabetes; recent advances in islet isolation and immunosuppression have led to greatly improved results. However, major obstacles and gaps in our current scientific knowledge preclude islet transplantation from being widely adapted as a treatment for type I diabetes. For example, islets within the pancreas are extensively vascularized and have a complex intraislet vascular network, but islet isolation severs arterial and venous connections. Transplanted islets must revascularize to obtain the nutrients and oxygen necessary for function and survival, but the molecular events of revascularization of transplanted islets are incompletely characterized and interventions to improve islet revascularization are not known. The rapidity and degree of revascularization of transplanted islets will greatly influence the survival and function of transplanted islets and whether the surviving islet mass is sufficient to reverse diabetes. Furthermore, studies of the revascularization of human islets are extremely limited. The proposed studies are an integrated effort by investigators with diverse scientific backgrounds (human islet isolation, islet physiology and biology, biomedical engineering, and angiogenesis) to better understand the molecular events of revascularization of human islets. Using gene transfer technology and an immunodeficient mouse model that allows for in vivo study of xenotransplanted human islets, we propose to test two hypotheses: 1) revascularization of human pancreatic islets after transplantation will be promoted by angiogenic factors and receptors involved in normal angiogenesis and the vascularization of tumor micrometastases; 2) improved revascularization will increase the survival and function of transplanted islets. Our xenograft model allows examination of molecular events that cannot be studied in patients who have undergone islet transplantation and since the recipient of the human islets is a mouse, a number of powerful experimental techniques (transgenes, gene knockouts, etc.) may be introduced to improve the study of molecular mechanisms. The proposed studies should lead to better understanding of the molecular events involved in revascularization of transplanted islets and enhance islet transplantation in humans.