从KCNK3钾通道转运障碍探讨肺动脉高压新的发病机制和治疗策略

项目名称： 从KCNK3钾通道转运障碍探讨肺动脉高压新的发病机制和治疗策略

项目编号： No.81470251

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： 毛卫克

作者单位： 华中科技大学

项目金额： 70万元

中文摘要： 肺血管平滑肌细胞（PASMC）过度增殖及血管重塑是肺动脉高压的突出特点，肺特异性表达的缺氧诱导的丝裂原因子（HIMF）可介导上述过程，但其作用靶点及机制远未阐明。最新研究发现PASMC上一种对缺氧、酸敏感的钾通道-KCNK3在膜上表达/功能丧失可能是肺动脉高压发病的独立始发因素，而KCNK3膜前向转运障碍下调其膜表达量。据此假设：肺缺氧时通过HIMF介导的信号途径引起KCNK3胞内转运障碍、膜表达/功能下调、肺血管强烈收缩、过度增殖是发病的重要机制。本课题分别以离体培养平滑肌细胞和活体肺高压大鼠为实验平台，首先探明缺氧/HIMF刺激下调膜KCNK3表达/功能与细胞过度收缩、增殖间的关系，然后进一步验证HIMF增强KCNK3分子特定位点磷酸化是造成其胞内转运障碍，膜表达下调的原因；最后尝试用干扰RNA技术下调HIMF作为干预策略的可行性，为确定肺动脉高压新的发病机制和治疗靶点提供理论依据。

中文关键词： 肺动脉高压；肺动脉平滑肌细胞；离子通道；缺氧；信号通路

英文摘要： xcessive proliferation in pulmonary vascular smooth muscle cells (PASMC) and vascular remodeling are the significant characteristics of pulmonary hypertension (PAH), which can be mediated by hypoxia-induced mitogenic factor (HIMF) specifically expressed in lung. But its targets and mechanisms are not clarified. Recent studies has found that the functional loss of KCNK3, a acid and hypoxia sensitive potassium channel expressed on PASMC, may be one of the independent initial factors in pathogenesis of pulmonary hypertension and dysregulation of intracellular KCNK3 trafficking decreases its expression in cell membrane. Based on the evidence above we hypothesize that pulmonary hypoxia causing abnormal KCNK3 intracellular trafficking and downregulated membrane express/function through HIMF related signal pathway is the important molecular mechanisms underlying PASMC excessive contraction/proliferation. In tis proposal we will use both cultured PASMC in vitro and rat PAH model in vivo as our experimental platform. We will firstly study the relationship between hypoxia/HIMF induced downregulation of functional KCNK3 and abnormal cell contraction/proliferation, then further validate that HIMF caused abnormal KCNK3 trafficking and downregulation of expression/function is mediated by specific phosphorylation changes in KCNK3 molecule. Finally， by using RNA interference technology to silence HIMF as the feasibility of an intervention strategy, this proposal will provide the theoretical basis for elucidating new mechanisms and therapeutic targets of pulmonary hypertension.

英文关键词： pulmonary hypertension;PASMC;ion channel;hypoxia;signal pathway