张应变诱导的内皮源性微体在血管平滑肌细胞增殖和凋亡调控中的力学生物学机制

Recent studies have demonstrated that levels of endothelial microparticles (EMPs) were significantly augmented in hypertension patients. However, the role of pathological stretch induced EMPs in hypertension is still not clear. In this project, we will conduct systematic studies on the spatial distribution and instantaneous dynamics of Src and FAK activated by stretch-induced EMPs, and further reveal their roles in proliferation and apoptosis of recipient VSMCs. In order to finish above studies, three key techniques: FX-5000T strain system, fluorescence resonance energy transfer (FRET) technique and gain-of-function and loss-of-function methods will be used in this project. Firstly by conducting proteomics studies, the important signal pathway of Src and FAK will be constructed; Secondly, gain-of-function and loss-of-function methods are utilized to identify the effect of key molecules in regulating cell functions; finally, the hypertension animal models are utilized to identify the in vivo role of reconstructed EMPs in hypertension vascular remodeling. In this project, we will investigate the in-depth mechanobiological mechanism of stretch-induced EMPs on the spatio-temporal activation of Src and FAK in recipient VSMCs, and reveal their roles in regulating cell proliferation and apoptosis. Above fundamental studies will contribute in revealing the pathological mechanisms of hypertension vascular remodeling by providing important and solid mechanobiological evidences, which is of significant importance in developing potential medicine and clinical treatments for hypertension patients.

高血压患者内皮源性微体（EMPs）分泌显著升高，而目前对高血压病理张应变诱导的EMPs在高血压血管重建中的作用尚不清楚。本项目拟在前期蛋白质组学的基础上，应用体外培养细胞张应变加载系统、荧光共振能量转移（FRET）技术、特异性分子的功能获得或功能缺失方法，以靶细胞－平滑肌细胞（VSMCs）内Src和FAK为切入点，探讨不同张应变诱导的EMPs对靶VSMCs内Src和FAK的动态激活过程和时空分布的影响，探讨EMPs表面分子在靶VSMCs内Src和FAK激活中的作用；研究高张应变诱导的EMPs对VSMCs增殖和凋亡的调控作用及分子机制；最后回归动物水平验证改变关键节点分子的EMPs在高血压动物血管重建中的作用。本项目拟研究EMPs这一新型细胞间信息交流载体，关注张应变调控的EMPs对靶VSMCs信号激活的始动阶段及其时空效应，为揭示高血压血管重建的病理机制提供重要的力学生物学依据。

高血压等心血管疾病患者体内微体（MPs）分泌水平显著升高，而目前对病理条件下分泌的MPs在高血压等心血管疾病血管重建中的作用尚不清楚。本项目结合蛋白质组学和生物信息学分析，应用体外培养细胞张应变加载系统、荧光共振能量转移（FRET）技术、细胞分子细胞学等技术，以靶细胞－平滑肌细胞（VSMCs）内Src和钙为切入点，探讨不同MPs对靶VSMCs内Src和钙的动态激活过程和时空分布的影响，探讨MPs在靶细胞的作用位点和信号转导通路；研究MPs对VSMCs凋亡等重要细胞功能的调控作用及分子机制；最后回归动物水平验证阻断关键响应分子在血管重建中的作用。本项目拟研究MPs这一新型细胞间信息交流载体，关注其对血管重建中重要细胞功能的调控作用及机制，为揭示高血压等心血管疾病血管重建的病理机制提供重要的力学生物学依据。.