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

SLIT-ROBO 和 MT1-MMP 在 MSC 介导的新血管形成中的作用。

基本信息

批准号：
9889392
负责人：
Ming-Sing Si
金额：
$ 16.96万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9889392
关键词：
Applications Grants Area Autocrine Communication Award Axon Basic Science Behavior Biological Assay Blood Vessels Cardiac Surgery procedures Cardiovascular Diseases Cardiovascular system Cell Mobility Cells Cellular biology Clinical Clinical Trials Committee Members Data Defect Development Disease model Endothelial Cells Experimental Designs Extracellular Matrix Foundations Functional disorder Genes Genetic Heart Heart failure Home environment Human Resources In Vitro Injury International Invaded Investigation Ischemia K-Series Research Career Programs KDR gene Knowledge Laboratories Left ventricular structure LoxP-flanked allele MMP14 gene Manuscripts Mediating Membrane Mentors Mentorship Mesenchymal Stem Cells Metalloproteases Methods Modeling Mus Natural regeneration Peptide Hydrolases Pericytes Physiologic intraventricular pressure Play Publishing Recovery Regulation Reporting Research Research Personnel Research Training Resources Role Schedule Scientist Signal Transduction Site Snails Stress Therapeutic Therapeutic Effect Therapeutic Intervention Time Tissues Training Training Programs Transcriptional Activation Transgenic Mice Writing angiogenesis autocrine axon guidance base career cell behavior cell motility conditional knockout constriction design experience heart function improved in vivo injured insight interest mouse model neovascularization novel novel therapeutics paracrine pressure professor programs response responsible research conduct skills slug stem cell biology symposium tissue injury tissue regeneration trafficking transcription factor

项目摘要

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.

项目总结