组蛋白去乙酰化酶抑制剂保护烧伤后血管内皮细胞屏障的作用和机制研究

项目名称： 组蛋白去乙酰化酶抑制剂保护烧伤后血管内皮细胞屏障的作用和机制研究

项目编号： No.81471872

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 胡森

作者单位： 中国人民解放军总医院

项目金额： 72万元

中文摘要： 保护血管内皮屏障（VEB）功能，对于减轻烧伤引起的血浆渗出和组织水肿、防治休克有重要意义。烧伤组织缺氧和高温能激活缺氧诱导因子1（HIF-1）/热休克蛋白90(HSP90)信号通路，增强下游靶基因血管内皮屏障调节因子的转录，增加肌球蛋白轻链磷酸化，导致内皮骨架蛋白收缩，损害VEB功能。以往研究表明，组蛋白去乙酰化酶抑制剂（HDACI）能抑制HIF-1/HSP90，但其对烧伤VEB损害的作用及机制尚不清楚。我们假设HDACIs能通过下调HIF-1α/HSP90，稳定内皮细胞骨架，保护VEB功能。研究目标：①采用内皮细胞低氧、高温培养和烧伤血清刺激，确认HDACIs对VEB有保护作用; ②研究HDACI通过下调HIF-1α及其共刺激分子的乙酰化水平和抑制HSP90的分子伴侣作用，降低HIF-1的功能、保护VEB的机制。③制作严重烧伤动物模型验证HDACIs减少渗出和补液量、防治休克的效果。

中文关键词： 严重烧伤；血管内皮细胞；组蛋白去乙酰化酶抑制剂；缺氧诱导因子；热休克蛋白

英文摘要： The protection of vascular endothelial barrier (VEB ) from damage caused by major burn injury is of great importance in the prevention and treatment of shock and tissue edema. Emerging evidence suggests that hypoxia and hyperthemia activate the hypoxia-inducible factor-1(HIF-1)/heat shock protein 90 (HSP90) signaling pathway which promotes the transcription of downstream gene vascular-endothelial-barrier regulating-factors which have been demonstrated to be strong regulators involved in endothelial skeleton loose and systolic dysfuction. Histone deacetylase inhibitors (HDACIs), have recently been shown to be able to prevent the skeleton protein contraction and inhibit HIF-1/HSP90, but their protective effects and mechanism of burn-induced VEB damage remain unknown. We assume that the HDACIs may possibly protect VEB function through inhibiting HIF-1 alpha/HSP90 function leading to stabilizing endothelial skeleton. The objectives of this research are: 1. to confirm whether or not HDACIs can protect endothelial barrier function from hypoxia/hyperthemia/burn serum-induced injury in a cultivated endothelium; 2. to investigate the mechanism by down-regulatoery effects on and the acetylation levels of HIF-1 and its stimulus molecule, as well as the synergy of HSP90 as molecular chaperone; and 3. to explore the therapeutic potential of HDACIs in treating severe burn-induced plasmexhidrosis and tissue edema due to VEB dysfunction.

英文关键词： severe burn injury;vascular endothelial cell;histone deacetylase inhibitor;hypoxia-inducible factor;heat shock protein