盐敏感性高血压(SSH)及其引发的并发症严重危害人类健康。研究提示交感神经活动增强与SSH发病密切相关，亦是目前的研究热点。下丘脑室旁核和食欲素1型受体(OX1R)在交感神经活动及血压的调控中起重要作用。申请者前期研究显示，高盐饮食可显著上调盐敏感大鼠室旁核内OX1R表达，而其作用及机制尚不清楚。最新研究显示，OX1R激活可通过MAPK通路参与中枢神经系统调控，MAPK通路激活可促进胞内促炎细胞因子(PICs)表达。由此推测：高盐饮食可激活室旁核内OX1R/MAPK/PICs通路，增强交感神经活动，继而诱发SSH发生。本项目拟构建含OX1R和OX1R-shRNA重组腺相关病毒，采用体内外实验系统研究上调/下调室旁核内OX1R表达，观察对盐敏感大鼠交感神经活动和血压影响，以及相关基因和蛋白的表达变化。旨在深入探讨OX1R激活诱发交感神经活动增强及血压升高的新机制，为SSH临床防治提供新策略。

Salt-sensitive hypertension (SSH) and associated complications are serious threat to human health. The enhanced sympathetic nerve activity is implicated to be closely related to the SSH, and currently this is a hot research topic. It has been reported that the paraventricular nucleus of hypothalamus (PVN) and the orexin type 1 receptor (OX1R) played an important role in the regulation of sympathetic nerve activity and blood pressure. Our preliminary results suggest that high-salt diet significantly up-regulated the expression of OX1R in the paraventricular nucleus of salt-sensitive rats, but the underlying mechanism is unclear. The latest studies suggest that activation of OX1R regulates central nervous system through MAPK signal pathway, and the activation of MAPK pathway is implicated in promoting the expression of intracellular proinflammatory cytokines (PICs). Therefore, we hypothesize that high-salt diet can activate the OX1R/MAPK/PICs pathway in the paraventricular nucleus, enhance the sympathetic nerve activity, and further induce the development of SSH. In this study, we will construct a recombinant adeno-associated virus containing OX1R or OX1R-shRNA to increase or decrease the expression of OX1R in vivo and in vitro, and investigate the effects of OX1R upregulation and downregulation on the sympathetic nerve activity, blood pressure, and the changes of related gene and protein expression in Dahl salt-sensitive rats. The purpose of the study is to explore the underlying new mechanism involved in the enhanced sympathetic nerve activity and elevated blood pressure induced by OX1R activation. This study will provide a novel strategy for clinical prevention and treatment of SSH in the paraventricular nucleus.