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。

• 批准号: 10064102
• 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
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2021-07-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064102
• 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; 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 therapeutic intervention; paracrine; pressure; professor; programs; regeneration function; response; responsible research conduct; skills; slug; stem cell biology; symposium; tissue injury; tissue regeneration; trafficking; transcription factor

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.

项目摘要 这是K08指导的临床科学家职业发展奖的申请，旨在培训Ming-Sing Si博士， 心脏手术的助理教授。 SI博士对科学研究有浓厚的兴趣，如 通过他在教育生涯的每个阶段参与研究的长期记录。 SI博士 部门已确保他受保护的时间，实验室空间，人事支持和所有其他资源 需要成功完成此培训计划。拟议的培训计划将为SI博士提供 成为成功关注间充质干细胞（MSC）的成功独立研究者的必要技能 和血管周细胞生物学。培训的关键组成部分将包括高级研究生级课程 实验方法，组织再生和负责任的研究，先进的就业 实验设计中的遗传方法和新型转基因小鼠模型，经常计划的相互作用 凭借他的精通委员会成员，开创性和会议参与，手稿写作，R01 Grant 提案写作以及对新生血管中的MSC/血管周围细胞功能的基础科学研究 tion。 Mentalship委员会由三名与MSC有关的国际知名专家组成 naling和血管生成。这些专家在为年轻临床医生和 科学家。申请人收集了初步数据，这些数据暗示了Slit-Robo信号传导，这是一个信号轴 轴突和尖端内皮细胞，与新血管形成和组织再生有关的MSC行为。基于 关于这些发现和相关发表的结果，他的一位导师关于MT1-MMP的重要性和 细胞侵袭中的蜗牛转录因子，适用的计划定义了如何以及在多大程度上缝隙 - 裂口 信号传导和MT1-MMP在体外和体内刺激MSC介导的血管生成，并利用这种知识 设计有效刺激新血管形成的新型热策略。具体目的 项目是：（1）确定slit3-robo1信号传导对MSC运动，侵入性，胶原溶解的影响 和左通气（LV）压力超负荷的情况下的血管生成。 （2）定义MT1-MMP的作用 MSC侵入性MSC介导的血管生成和心力衰竭。 （3）表征体内的本地角色 LV压力超负荷期间使用条件基因敲除小鼠，血管周壁细胞-SLIT3-ROBO1轴 型号。这项研究将在多细胞的情况下提高对血管生成反应的理解 相互作用，应该为治疗性新血管化的手段提供宝贵的见解 被引起。拟议的研究和培训计划的完成将提供知识和经验 为了使适用于MSC生物学，血管生成和心脏的独立研究者 血管再生。具体而言，拟议研究的数据将作为R01的基础 申请将在K08奖励的第三年提交，该申请将探讨Slit-Robo的功能 在心血管疾病的情况下，MSC/周细胞中的信号传导。