项目名称: GIT1对心肌细胞能量代谢的调控机制及其在心力衰竭中的作用
项目编号: No.81470514
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: 庞锦江
作者单位: 同济大学
项目金额: 73万元
中文摘要: 心力衰竭是一种复杂的病理生理过程。近年研究发现线粒体功能障碍参与了心肌肥厚和心力衰竭的过程,其中PGC-1表达异常会造成线粒体合成功能障碍和加剧氧化应激,从而导致心肌肥厚和心力衰竭。GIT1做为支架蛋白,能直接与信号分子相互作用,并在不同的细胞中调节不同的信号通路。我们前期研究发现GIT1调节CamKI和HDAC5磷酸化并促进PGC-1表达,提示GIT1可能通过CamKI-HDAC5-PGC-1参与心肌肥厚心力衰竭的发病机制。本项目拟通过牵张刺激胚胎期心室肌细胞和H9C2细胞,结合线粒体功能检测、Western blot、免疫共沉淀和荧光素酶报告基因等方法阐明GIT1对CamKI-HDAC5-PGC-1通路的调节机制。另外通过心脏特异性GIT1基因敲除小鼠,明确GIT1在心肌肥厚和心力衰竭中的作用及可能参与机制,为心肌肥厚和心力衰竭的防治提供新的分子靶点。
中文关键词: 心肌肥厚;心肌细胞;GIT1;慢性心力衰竭
英文摘要: Heart failure is a complex pathophysiological process. Recently, it is showed that mitochondria dysfunction plays a critical role in this process. PGC-1 dysregulation results in impaired mitochondrial biogenesis and enhancd oxidative stress, which is essential for the progress of cardiac hypertrophy and heart failure. As a scaffold protein, GIT1 directly interacts with signal molecules and regulates different signaling pathways. Our preliminary data suggest that GIT1 is required for PGC-1 expression through CamKI-HDAC5 pathway, implying that GIT1 is involved in pathogenesis of cardiac hypertrophy and heart failure. In current proposal, we will use embryonic cardimyocytes and H9C2 cells challenged with stretch to study the role of GIT1 in CamKI-HDAC5-PGC-1α signaling by measuring mitochondrial function, western blot, co-immunoprecipitation, luciferase reporter assay and so on. In addition, we will determine the role of GIT1 in cardiac function using cardiac specific GIT1 knockout mice. Our study will provide new therapeutic target for cardiac hypertrophy and heart failure.
英文关键词: cardiac hypertrophy;cardiomyocytes;GIT1;Chronic heart failure