Many reports indicate the number of people with diabetes will exceed 350 million by the year 2030. Both type 1 and type 2 diabetes are characterized by the deterioration and impaired function of pancreatic b-cells. While transplantation is a promising strategy to replace lost tissue, several obstacles remain in the pathway to its clinical application. Whether b-cells are derived from patient samples or differentiated from embryonic stem cells, a major concern facing these strategies is how a recipient will respond to transplanted foreign tissue. Since the native environment for pancreatic islets is comprised of neural and vascular networks, successful integration may depend upon signals received from these neighboring cell types. Using a multidisciplinary approach, the principal investigator plans to elucidate molecular mechanisms underlying the interactions between pancreatic islet cells and their neighboring endothelial cells. Developing an understanding of how these interactions change during the pathogenesis of disease will provide insight into how islet growth and insulin release is dependent upon signals received from adjacent cell types. Emphasis will be placed on genetic mouse models to measure changes in gene expression in both isolated pancreatic b-cells and endothelial cells to identify genes that mediate the interaction between these cell types. In addition, it is of great interest to identify secreted factors that may constitute autocrine or paracrine signalling mechanisms that influence growth and function between these cell types. Furthermore, it will be determined whether current protocols for the differentiation of mouse stem cells into insulin producing cells are improved by restoring the expression of genes which facilitate communication to endothelial cells. This project aims to identify genes essential to the vascular context of pancreatic b-cells to improve transplantation protocols and facilitate the development of therapeutic strategies for diabetes.