Role of SLIT-ROBO and MT1-MMP in MSC-Mediated Neovascularization

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PROJECT SUMMARY This is an application for a K08 Mentored Clinical Scientist Career Development Award to train Dr. Ming-Sing Si, an Assistant Professor in Cardiac Surgery. Dr. Si has a strong interest in scientific investigation, as demonstrated by his long track record of participation in research throughout every stage of his educational career. Dr. Si’s Department has guaranteed him protected time, laboratory space, personnel support, and all other resources required to complete this training program successfully. The proposed training program will provide Dr. Si the necessary skills to become a successful independent investigator focused on mesenchymal stem cell (MSC) and perivascular cell biology. Key components of the training will include graduate level courses in advanced experimental methods, tissue regeneration, and responsible conduct of research, incorporation of advanced genetic methods and novel transgenic mouse models in experimental design, frequent scheduled interactions with his mentorship committee members, seminar and conference participation, manuscript writing, R01 grant proposal writing, and basic science investigation into the function of MSC/perivascular cells in neovasculariza- tion. The mentorship committee is comprised of three internationally renowned experts relevant to MSCs, sig- naling, and angiogenesis. These experts are also experienced in providing mentorship to young clinicians and scientists. The applicant has gathered preliminary data that implicate SLIT-ROBO signaling, a signaling axis for axons and tip endothelial cells, in MSC behavior pertinent to neovascularization and tissue regeneration. Based on these findings and related published results from one of his mentors on the importance of MT1-MMP and Snail transcription factors in cell invasion, the applicant plans to define how, and to what extent, SLIT-ROBO signaling and MT1-MMP stimulate MSC-mediated angiogenesis in vitro and in vivo, and to utilize this knowledge to design novel therapeutic strategies that effectively stimulate neovascularization. The specific aims for this project are: (1) Determine the effects of SLIT3-ROBO1 signaling on MSC motility, invasiveness, collagenolysis, and angiogenesis in the setting of left ventricle (LV) pressure overload. (2) Define the role of the MT1-MMP on MSC invasiveness MSC-mediated angiogenesis and heart failure. (3) Characterize the in vivo, native roles of the perivascular mural cell-SLIT3-ROBO1 axis during LV pressure overload using conditional knockout mouse models. This research will advance the understanding of angiogenic responses in the setting of multicellular interactions and should provide valuable insights into the means by which therapeutic neovascularization can be elicited. The completion of the proposed research and training plan will provide the knowledge and experience for the applicant to become an independent investigator in the field of MSC biology, angiogenesis, and cardio- vascular regeneration. Specifically, the data from the proposed study will serve as the foundation for an R01 application to be submitted during the third year of the K08 award that will explore the function of SLIT-ROBO signaling in MSC/pericytes in the setting of cardiovascular disease.