申请人长期开展“环境应激源诱导应激损伤及健康危害的基因表达调控机制”研究工作，近年来在“PM2.5诱发呼吸系统损伤效应机制”研究中取得了系列创新性研究发现。以此为基础，申请人近期又在“PM2.5致心血管系统损伤效应机制”的体内外研究中获得了重要线索，发现了PM2.5暴露能够诱导血管内皮细胞中肾素-血管紧张素系统（RAS）关键成分ANGII、ACE和AT1R表达水平上调并促发后续的血管内皮功能紊乱效应。另外，IRE-1a/XBP1s介导的内质网应激能够偶联HIF1a协同介导上述RAS成分的诱导表达反应；而应激损伤保护因子HO-1能够拮抗RAS成分的诱导表达。本项目拟定基于上述研究线索继续深入探究IRE-1a/XBP1s/HIFa途径和HO-1分别参与调控RAS成分异常扰动和血管内皮损伤反应的信号转导网络，为PM2.5致心血管系统健康危害效应机制研究及损伤防控策略研究提供崭新内容。

I have long been engaged in the basic research to disclose the signaling mechanism involving in cellular stress responses and adverse health effects induced by the environmental risk factors, such as arsenite, ultraviolet and fine particulate matters (PM2.5). Findings from my recent research have revealed the previous unidentified signaling network involving in mediating pro-inflammatory effects in the respiratory system triggered by PM2.5. After getting these results, I extended my research work to the cardiovascular (CV) system due to the potential adverse PM2.5 impact on the progression of various CV diseases. And our primary studies in this field have disclosed the aberrant up-regulation of AGT, ACE and AT1R, the major components of renin-angiotensin system (RAS), contributed largely to the induction of vascular endothelial dysfunction under PM2.5 exposure. Further investigations demonstrated that activation of IRE1α/XBP1s branch of endoplasmic reticulum stress was essential for augmented vascular RAS component expression in response to PM2.5 exposure, whose effects seemed synergistically exerted by the assembly of XBP1s/HIF1α transcriptional complex. Moreover, HO-1 induction inhibited the increasing of RAS components expression in the vascular endothelial cells under the same PM2.5 exposure conditions. The follow-up research work based on these previous clues is expected to disclose the roles of IRE-1a/XBP1s/HIFa pathway activation and HO-1 induction in regulating RAS components augmentation, which will be helpful to elucidate the complex pathological outcomes in the CV system originated from vascular endothelial dysfunction and to search the intervention strategies for alleviating disturbances associated with PM2.5 exposure.