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

项目总结 现申请K08临床科学家导师职业发展奖，以培训司明星博士， 心脏外科的助理教授。司徒华博士对科学研究有着浓厚的兴趣，正如所证明的那样 由于他在教育生涯的每个阶段都参与研究的长期记录。思博士的 部门已经保证了他受保护的时间、实验室空间、人员支持和所有其他资源 成功完成此培训计划所必需的。拟议的培训计划将为司徒华博士提供 成为一名成功的专注于间充质干细胞(MSC)的独立研究人员所需的技能 和血管周围细胞生物学。培训的主要组成部分将包括高级研究生课程 实验方法，组织再生，负责任地进行研究，纳入先进 实验设计中的遗传方法和新型转基因小鼠模型，频繁的程序性相互作用 与他的指导委员会成员，研讨会和会议的参与，手稿写作，R01拨款 提案撰写，以及对MSC/血管周围细胞在新生血管中的作用的基础科学研究- 提顿。指导委员会由三位与MSCs有关的国际知名专家组成，Sig. 纳灵和血管生成。这些专家在为年轻临床医生提供指导方面也很有经验 科学家。申请人已经收集了涉及狭缝-ROBO信号的初步数据，这是一个信号轴 轴突和尖端内皮细胞，在与新生血管和组织再生相关的MSC行为中。基座 关于这些发现和他的一位导师关于MT1-MMPs重要性的相关发表结果 蜗牛转录因子在细胞入侵中的作用，申请人计划定义如何以及在多大程度上，狭缝-ROBO 信号转导和MT1-MMP体内外刺激MSC介导的血管生成 设计新的治疗策略，有效地刺激新生血管。这方面的具体目标 项目包括：(1)确定SLIT3-Robo1信号对MSC的运动性、侵袭性、胶原分解、 左心室(LV)压力超负荷状态下的血管生成。(2)明确MT1-MMPs在细胞周期中的作用 MSC侵袭性、MSC介导的血管生成与心力衰竭。(3)描述在体内的、天然的作用 条件性基因敲除小鼠左心室压力超负荷时血管周围壁细胞-SLIT3-Robo1轴的变化 模特们。这项研究将促进对多细胞背景下血管生成反应的理解 并应提供有价值的见解，了解治疗性新生血管 被引诱。拟议研究和培训计划的完成将提供知识和经验 申请成为MSC生物学、血管生成和心脏领域的独立研究员- 血管再生。具体地说，拟议研究的数据将作为R01的基础 将在K08奖项的第三年提交的申请将探索狭缝机器人的功能 MSC/周细胞在心血管疾病中的信号转导。

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.