Pancreatic islets are extensively vascularized and this is likely important in their ability to sense the blood glucose and quickly secrete insulin. Although pancreatic islet function and vascularization are fundamentally linked, there are a number of unanswered questions and gaps in our knowledge about this process. For example, islets within the pancreas have a complex intraislet vascular network, but the factors that control the development of normal islet vasculature are incompletely defined. Furthermore, islet transplantation in humans has great promise as a treatment for type 1 diabetes, but islet isolation severs arterial and venous connections so transplanted islets must revascularize to obtain the nutrients and oxygen necessary for function and survival. Little is known about the sequence of molecular events and factors important for revascularization of transplanted islets and thus, interventions to improve islet revascularization are not known. Using a multidisciplinary approach involving developmental biology, transgenic technology and transplantation of murine and human islets, our team proposes two interrelated specific aims: 1) describe the molecules and fundamental events in islet vascularization and revascularization; 2) determine the role of two angiogenic factors, VEGF and Ang-1, in islet vascularization and revascularization of islets after transplantation. The studies will involve an in-depth analysis of the relationship between islet development and vascularization in genetically modified mice that allow for precise """"""""marking"""""""" of endothelial cells and in transgenic mice that express angiogenesis factors or inhibitors. These powerful experimental techniques emphasize the utility of such mouse models to address mechanistic questions. However, human and mouse islet differ, so the proposed studies also will integrate parallel studies with human islets transplanted into a xenograft model. The proposed studies bring three distinguished investigators from the vascular biology area (Bader/Baldwin/Lin) to work with two investigators already working in the area of type 1 diabetes and islet biology (Gannon/Powers). In addition to bringing together scientists from different disciplines (Endocrinology, Cell Biology, Cardiology, Pediatrics, Cancer Biology), the proposed studies also seek to apply rapidly expanding knowledge about angiogenesis and neovascularization from the developmental biology and cancer biology fields to improve islet revascularization. A better understanding of normal islet vascularization will provide insights into normal islet development, architecture, and function. This information may be pertinent to efforts to proliferate and expand islet stem cells and islets, all of which must become vascularized. In addition, the rapidity and degree of revascularization of transplanted islets greatly influences the survival and function of transplanted islets and whether the surviving islet mass is sufficient to reverse diabetes. We anticipate that information about islet revascularization from these studies will be directly relevant to transplantation in humans and will be useful in planning future interventions in humans.
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