Intrahepatic infusion of islets isolated from human donor pancreas is the commonly accepted method for reversal of diabetic hyperglycemia in clinical transplantation. The development of an alternate transplant site which could be conditioned by the localized administration of anti-inflammatory agents, and/or other compounds to induce neovascularization could facilitate use of fewer islets and consistent islet graft success using a single donor pancreas. Toward this end, the proposed research will elucidate the fundamental mechanisms by which sphingosine1-phosphate (S1P) receptor subtype signaling regulates adult microvascular remodeling in diabetic animal models. Diabetes is a well known and significant risk factor in the development of vascular disease, and diabetes is known to impair new blood vessel formation and endogenous neovascularization of ischemic tissue. Therefore, the proposed research specific aims will address the overarching hypothesis that selective pharmacological activation of S1P receptor subtypes S1P1 and S1P3 induces formation of mature microvascular networks in diabetic animals by promoting recruitment and proliferation of upstream mural support cells (smooth muscle cells and pericytes) on arteriole microvessels. Aim 1 will determine the role of selectively induced S1P1/S1P3 signaling during pharmacological induction of arteriogenesis in diabetic mouse dorsal skinfold window chambers; Aim 2 will determine the role of selective S1P1/S1P3 signaling during tissue ischemia and consequent arteriolar remodeling in diabetic mice using in a spinotrapezius model. The intellectual merit of the proposal concerns how selective activation of S1P receptor subtypes by engineered S1P receptor targeted compounds can be utilized to locally suppress early inflammatory events and induce neovascularization and topics critical to improving pancreatic islet transplant success. Moreover, as many significant aging associated diseases arise from impaired or abnormal function of microvasculature, the development of effective strategies to promote formation of mature microvascular networks is a critically important medical need with potential for transformative broader impact on treatment of many important diseases. Integrated education activities will emphasize cultivation and advising of integrated Capstone Design teams to 1) establish multiple peer-to-peer relationship that cross ethnic, cultural, and economic boundaries, 2) give students an appreciation for the impact that TE/RM applications can make on human health worldwide. A short course in regenerative medicine will also be developed and taught at the University of Ghana to cultivate greater participation in new "globally distributed design" teams within the NSF-sponsored BME Planet Network.
