miR141对RhoA、Rac1调节作用及其与休克血管反应性的关系

Vascular reactivity exists in clinical condition such as severe trauma and shock,this reduced vascular reactivity severely interferes with the treatment of shock and other clinical critical conditions,particularly for the application of vaso-active agents. Our previous studies advocated from NSFC demonstrated that RhoA and Rac1 played important roles in the occurrence of vascular hypo-reactivity after shock. The changes of miR141 were negatively correlated with vascular reactivity after shock, and miR141 diminished the protein expression of RhoA and Rac1. We hypothesize that miR141 participates in the occurrence of vascular hypo-reactivity via regulation of RhoA and Rac1. The mechanisms may be related with its interaction with mRNA 3` UTR for RhoA or regulating DNA methylation for Rac1. To test this hypothesis, with hemorrhagic shock model, 293T cell and vascular smooth muscle cell, we will study the role of miR141 in the regulation of vascular reactivity following shock and the relationship to RhoA and Rac1, and the regulating mechanisms of miR141 on the expression of RhoA and Rac1. The objective is tended to intensify the mechanism of vascular hypo-reactivity, provide the new modulation targets for the treatment fo shock.

严重创伤、休克存在血管低反应性，这种血管低反应性严重影响休克等临床危重病症的发生、发展及治疗。我们前期研究发现休克后不同时相点miR141的变化与血管反应性变化间呈显著负相关，miR141对RhoA、Rac1蛋白表达具有明显调节作用，结合本人前一国家自然科学基金证实RhoA、Rac1在休克血管反应性调节中的重要作用，推测miR141可能通过RhoA、Rac1参与对休克血管反应性的调节，有不同机制参与对它们的调控，对RhoA的调节可能主要通过mRNA 3'UTR，对Rac1的调节可能主要通过调节DNA甲基化来实现。为此本课题拟取失血性休克大鼠，293T细胞，血管平滑肌细胞，研究miR141对休克血管反应性的调节作用与RhoA、Rac1的关系；miR141调节RhoA、Rac1机制，包括mRNA和DNA水平。通过该研究拟进一步阐述创伤休克等血管反应性的调节机制，为创伤休克等的治疗提供新的靶点。

严重创伤、休克存在血管低反应性，这种血管低反应性严重影响休克等临床危重病症的发生、发展及治疗。本项目通过对miR141、miR124对休克血管反应性的调节作用与机制的研究，发现：①休克或缺氧后血管对活性药物的反应性和平滑肌细胞的收缩反应性均降低，miR141的变化与血管反应性变化呈明显正相关关系，而miR124的变化与血管反应性变化呈明显的负相关，改变miR141和miR124表达可明显改变休克后血管反应性；②机制研究发现miR124 和 miR141 可通过调节RhoA、Rac1参与对休克血管反应性的调节； miR124 和 miR141可作用分别作用于RhoA 和 Rac1的3′UTR进而调节RhoA, Rac1的表达，进而调节休克血管反应性；此外， miR124和miR141之间存在明显的交互作用，miR141可通miR124调节Rac1的表达，同时miR124可通过miR141调节RhoA的表达，进一步研究发现，转录因子在miR124和miR141交互作用中发挥重要作用。通过该研究进一步阐明创伤休克等血管反应性的调节机制，为创伤休克等的治疗提供新的靶点。该项目研究发表SCI论文2篇，（Am J Physiol,2016和Critical Care Medicine,2016）；培养硕士研究生一名；参加学术交流会议1次（南京军区总医院组织的Zhongshan International Surgical Infection Forum)。