骨形态形成蛋白4与瞬时受体电位离子通道蛋白信号转导通路在慢性低氧性肺动脉高压发病机制中的研究

项目名称： 骨形态形成蛋白4与瞬时受体电位离子通道蛋白信号转导通路在慢性低氧性肺动脉高压发病机制中的研究

项目编号： No.81200037

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： 李晓岩

作者单位： 广州医科大学

项目金额： 23万元

中文摘要： 大部分慢性肺疾病患者均存在不同程度的肺动脉压力增高-慢性低氧性肺动脉高压（CHPH）,慢性低氧导致肺部血管收缩增强和血管重构。肺动脉平滑肌细胞（PASMCs）的过度增殖是导致肺血管中层肥大、血管重塑的主要原因。我们研究小组已有研究成果证实慢性低氧促进钙池操纵性钙离子内流（SOCE）导致Ca2+浓度升高，引起PASMCs过度收缩及增殖；经典瞬时受体电位离子通道(TRP)蛋白TRPC1，4，6基因蛋白是构成钙池操纵性钙离子通道的蛋白亚单位。目前，我们研究发现低氧上调的骨形态形成蛋白4（BMP4）可促进TRPC1,4,6 mRNA及蛋白的表达，增加SOCE及Ca2+浓度。到目前为止，CHPH的发病机制仍未完全阐明，本课题将详细研究慢性低氧/BMP4/TRPC1,4,6/SOCE之间的关系，及所涉及的信号转导通路，为研发更加有效的预防及治疗CHPH的药物打下坚实的理论基础。

中文关键词： 骨形态形成蛋白；细胞内钙离子浓度；瞬时受体蛋白；信号通路；

英文摘要： Many or most chronic and progressive lung diseases involve Chronic hypoxic pulmonary hypertension which Chronic hypoxia causes pulmonary hypertension with vascular remodeling, increase in vascular tone and altered reactivity to agonists. Excessive proliferation in pulmonary arterial smooth muscle cells (PASMCs) is associated with profound vascular remodeling and middle pulmonary artery hypertrophy. The results from our group and other groups show that store-operated Ca(2+) entries (SOCE) in PASMCs are upregulated by chronic hypoxia and contribute to the enhanced vascular tone and PASMC over proliferation, and that canonical transient receptor potential channel (TRP) proteins- TRPC1, TRPC4, and TRPC6 which encode store-operated cation channels, play important roles in Ca(2+) regulation and cell proliferation. Recently, we found that Bone morphogenetic protein-4 (BMP4) upregulation induced by hypoxia increased TRPC1, TRPC4, and TRPC6 mRNA and protein, augmented SOCE and elevated basal [Ca(2+)]i. Future studies designed to elucidate an interaction between chronic hypoxia,BMP4,TRPC1, TRPC4,TRPC6 and SOCE, the signaling pathways involved may uncover novel preventive and therapeutic targets in chronic hypoxic pulmonary hypertension.

英文关键词： BMP4；Iintracellular Ca21 concentration；TRPC；Signal pathway；