转录因子p53在低氧性肺动脉高压发病中的作用机制研究

项目名称： 转录因子p53在低氧性肺动脉高压发病中的作用机制研究

项目编号： No.81470246

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： 王健

作者单位： 广州医科大学

项目金额： 75万元

中文摘要： 抑癌基因p53在细胞增殖、凋亡和衰老过程中发挥重要的调控作用。肺动脉平滑肌细胞（PASMC）的过度增殖、肺血管重塑是肺动脉高压（PH）的典型病理特征。研究表明p53蛋白能够抑制PH的发病，且与低氧诱导因子（HIF-1）可以相互调控。我们前期研究证实：慢性低氧性PH中HIF-1表达增加，通过上调BMP4表达增加TRPC蛋白的表达，导致钙池操纵性钙内流，([Ca2+]i)增加，PASMC增殖。本研究拟通过p53、HIF-1基因敲除鼠CHPH模型，验证p53在PH发病中的作用，阐明其作用机制是否与调节 HIF-1-BMP4-TRPC-SOCE-[Ca2+]i通路有关；深入研究低氧是否通过促进泛素连接酶-鼠双微体（MDM）2的表达或增强其活性而导致p53蛋白降解；探讨阻断MDM2与p53的结合、减少p53的降解对PH的防治作用。本研究将为揭示PH的发病机制提供新的理论线索，为PH防治探寻新靶点。

中文关键词： 肺动脉高压；低氧诱导因子；p53；鼠双微体2

英文摘要： The transcription factor p53 was originally recognized as an tumor suppressor, latter on demonstrated to play important roles in the process of aberrant cell cycle control, apoptosis, and senescence. Enhanced pulmonary arterial muscle cell proliferation is one of the most important physiological phenomenon in pulmonary hypertention. Recently, several studies demonstrated that p53 participates in the disease development of pulmonary hypertension (PH), especially through a feedback regulation with the crucial moleculae hypoxia-inducible factor (HIF-1). Enhanced pulmonary arterial smooth nuscle cell proliferation is considered as one of the most important physiological changes in the development of pulmonary hypertention (PH). During the past decades, we and others have demonstrated that hypoxia accumulated expression and elevated transcriptional activity of HIF-1 play indispensable role during the development of chronic hypoxia-induced pulmonary hypertension (CHPH). We further elucidated that HIF-1 could trigger the bone morphogenetic protein 4 (BMP4) signaling transduction, which increases expression of transient receptor potential cation channel (TRPC), leading to enhanced SOCE, and eventual increased proliferation of pulmonary arterial smooth muscle cells (PASMCs). Enhanced PASMCs proliferation is considered as one of the most important physiological changes during PH disease pathogenesis. In this project, by using cultured rat distal PASMCs for in vitro experiment, CHPH animal models, as well as transgeneic animal model of p53 and HIF-1α, accompany with a series of molecular biological strategies, we sough to determine: 1) if hypoxia downregulates p53 in the pathogenesis of CHPH; 2) if p53 inhibits HIF1-BMP4-TRPC signaling axis in CHPH; 3) if overexpression or induction of p53 protects animals from CHPH development. Additionally, we will make efforts to clarify the p53 ubiquitin-proteasome degradation pathway and evaluate whether inhibition of p53 degradation could effectively relieve CHPH.

英文关键词： pulmonary hypertension;hypoxia-inducible factor;p53;murine double minute 2