PPP2R3A基因突变致家族性扩张型心肌病的分子机制研究

项目名称： PPP2R3A基因突变致家族性扩张型心肌病的分子机制研究

项目编号： No.81460064

项目类型： 地区科学基金项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 宋贵波

作者单位： 昆明医科大学

项目金额： 43万元

中文摘要： 家族性扩张型心肌病（FDCM）是以心室扩大和心肌收缩功能受损为特征的遗传性心肌病，是心力衰竭、猝死的重要原因和心脏移植的主要适应证。其发病机制不明，迄今发现的致病基因只能解释50％的患者。我们前期实验发现PPP2R3A基因突变与FDCM发病相关。本研究将进一步探讨其分子致病机制，为FDCM的基因诊断、发病机制的认识和治疗提供理论和实验依据。拟：1.在100例扩张型心肌病家系先证者或散发患者中筛查PPP2R3A基因的新突变位点；2.研究PPP2R3A过表达和敲减表达对心肌细胞增殖、凋亡的影响；3.筛选PPP2R3A的心肌互作蛋白，研究PPP2R3A基因突变对互作蛋白磷酸化状态及相关信号通路分子的影响，从分子、细胞水平探讨致病机制；4.利用PPP2R3A基因敲除小鼠，模拟疾病表型，分析病变心肌细胞中互作蛋白磷酸化状态及相关信号通路分子表达情况，从动物水平揭示发病机制。

中文关键词： 扩张型心肌病；分子机制；基因突变；PPP2R3A

英文摘要： Familial dilated cardiomyopathy is an inherited cardiomyopathy characterized by ventricular chamber enlargement and impaired systolic function. FDCM is the important cause of heart failure,sudden death and the major indication of heart transplantation.The exact pathogenesis of FDCM remains elusive.To date,known genes only explain the genetic background of 50% FDCM cases.We have previously found that PPP2R3A mutation was associated with FDCM.In order to further explore the molecular mechanisms, which will provide the theoreticaland experimental basis for gene diagnosis, an increasing understanding of the pathogenesis and treatment of FDCM.We would like to: 1.screen the new PPP2R3A mutations in 100 DCM probands or sporadic patients; 2.study the effects of overexpression and knockdown of PPP2R3A on cardiomyocyte proliferation and apoptosis; 3.identify the cardiac interacting protein of PPP2R3A;evaluate the effects of PPP2R3A mutations on phosphorylation status of interacting protein and related signaling pathway molecules,which will elucidute the pathogenic mechanism from the molecular and cellular aspects; 4.use PPP2R3A gene knockout mice to simulate the disease phenotype of DCM, then determine the phosphorylation status of interacting protein and expression level of related signaling pathway molecules,which will reveal the pathogenic mechanism in animals.

英文关键词： dilated cardiomyopathy;molecular mechanism;gene mutation;PPP2R3A