Mesenchymal Stromal Cells Modulate Intestinal Mesenteric Endothelium Via Hydrogen Sulfide

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PROJECT SUMMARY This new investigator proposal describes a 4 year training program for the development of a surgeon scientist career in Pediatric Surgery. The main focus of this new investigator’s work is on stem cell biology and stem cell therapy for the treatment of end organ ischemia. He is currently an Assistant Professor of Surgery at the IUSOM. His career goals are to use this K08 award to support his commitment to develop as a highly skilled scientist and in the long term to transition to a successful, independent, NIH-funded surgeon scientist. The IUSOM has guaranteed the applicant 75% protected time to commit to his research effort. In addition to the time commitment, the institution has provided an ample start-up package for the applicant, which includes lab space, research funds, and ancillary support for 5 years. The cornerstone of the career development plan is an exemplary scientific advisory committee. The five scientists are from diverse backgrounds and each is considered an international authority in their field. They have a long track record of supporting young scientists and providing effective mentorship. The candidate, in close consultation with the committee, has outlined an education plan that includes additional coursework, weekly lab meetings, national conferences, and an organized research plan to complete his training. The proposal investigates the underlying mechanism associated with mesenchymal stromal cell mediated intestinal protection following ischemic injury. The applicant developed a novel hypothesis that proposes that end organ intestinal protection is mediated by the stromal cell release of hydrogen sulfide gas, which works through efferent pathways, such as eNOS, to promote improved mesenteric perfusion. In testing of this hypothesis, two aims are outlined. Aim 1 is to define the role of hydrogen sulfide as a key stromal cell paracrine mediator in facilitating host protection following intestinal I/R. Aim 2 then attempts to elucidate the downstream mechanism that hydrogen sulfide utilizes on the mesenteric endothelium to promote improved perfusion following ischemia. {The proposal investigates nitric oxide as such a mechanism, and looks to determine if improved perfusion is due to mesenteric vasodilation, improved endothelial barrier function, or decreased leukocyte trapping within the microvasculature. These data will serve as ample transition into mechanistic testing for a future R01, in which a specific cysteine residue on eNOS will be mutated in order to generate a transgenic mutant mouse for invivo testing.} In summary, this research and training proposal aim to understand the molecular mechanisms associated with stromal cell mediated intestinal protection following intestinal ischemia. The grant, in conjunction with an expert and experienced mentoring panel, as well as strong institutional support from the IUSOM, would provide a highly innovative, supportive platform for this young surgeon-scientist to finish his scientific training and make the transition to independent investigator in the field of stem cell therapy and regenerative medicine.