MAPK通路在气道高反应性发生中对G-蛋白偶联受体的调控机制

项目名称： MAPK通路在气道高反应性发生中对G-蛋白偶联受体的调控机制

项目编号： No.81200001

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学一处

项目作者： 雷莹

作者单位： 西安交通大学

项目金额： 24万元

中文摘要： 气道高反应性是指气道对收缩性激动剂反应性的增加，是哮喘的典型特征。气道平滑肌细胞中的G-蛋白偶联受体参与了气道高反应性的发生。丝裂原活化蛋白激酶（MAPK）通路在气道平滑肌细胞内信号转导中起着关键的作用。我们假设气道炎性细胞因子通过影响MAPK通路信号分子，调控气道平滑肌中G-蛋白偶联受体功能，或调控G-蛋白偶联受体介导的钙离子通道从而改变气道平滑肌张力引起气道高反应性的发生。本项目拟用小鼠哮喘和吸烟模型和人支气管平滑肌细胞作为研究对象，通过在体给予MAPK通路上下游的抑制剂，观察气道反应性与G-蛋白偶联受体的表达和炎性因子表达的关系；通过抑制细胞中MAPK通路分子的表达，观察在炎性因子的作用下支气管平滑肌细胞G-蛋白偶联受体表达与及其介导的细胞内钙离子信号的变化。揭示气道炎症中，气道平滑肌G-蛋白偶联受体表达变化的调控机制，在细胞内炎性信号通路的水平寻求防治气道高反应性疾病的新靶点。

中文关键词： G-蛋白欧联受体；气道高反应性；哮喘；MAPK；炎性因子

英文摘要： Airway hyperresponsiveness consists of an increased sensitivity of the airways to constrictor agonists, which is the major feature of asthma. The airway G-proten coupled receptors like bradykinin receptors, thromboxane A2 (TP) receptors and endothelin receptors, which mediate the airway contractions, may play an important role in the development of the airway hyperresponsiveness. Mitogen-activated protein kinases (MAPK) pathway plays an important role in the intracellular signal transduction in airway smooth muscle cells. We hypothesized that the inflammatory cytokines induce the airway hyperresponsiveness by regulating the expression of airway G-protein coupled receptors and the intracellular calcium level via MAPK pathways. The present study is designed to examine the effects of Raf/MAPK/IKK inhibitors on airway responsiveness, airway G-protein coupled receptors expression and inflammatory cytokines expression in vivo by using murine asthma and smoking models; to examine the effects of Raf/MAPK/IKK inhibitors on intracellular inflammatory cytokine expression and the G-protein coupled receptors-mediated intracellular calcium levels by using human bronchial smooth muscle cells in vitro. The aim of the present study is to uncover the regulatory role of MPAK pathway on G-protein coupled receptors in airway hyperre

英文关键词： G-protein coupled receptors；airway hyperresponsiveness；asthma；MAPK；inflammatory cytokines