转录共调节因子Ddx17在心肌细胞损伤中的调控作用及机制的研究

项目名称： 转录共调节因子Ddx17在心肌细胞损伤中的调控作用及机制的研究

项目编号： No.81470427

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： 沈涛

作者单位： 北京医院

项目金额： 73万元

中文摘要： 心肌损伤是心力衰竭发生的重要原因之一，多种转录共调节因子在心肌损伤时发挥调节作用。Ddx17是在心脏表达丰富的转录共调节因子，但它在心肌损伤时的作用目前尚不清楚。我们前期研究发现：在心衰患者和小鼠模型中，Ddx17表达降低，同时心肌细胞凋亡增加；而心肌细胞过表达Ddx17后，细胞凋亡下降；通过蛋白质共沉淀结合质谱分析方法， 我们发现Ddx17可以与核受体3B1（NR3B1）结合，并提高其转录活性和表达。据此我们提出假说：Ddx17可能通过NR3B1调节心肌细胞能量代谢和氧化应激，抑制心肌损伤和心力衰竭发生。本研究拟从分子、细胞和整体水平，利用心肌细胞损伤模型、心力衰竭的动物和患者标本，以基因过表达、RNA干扰、免疫组化、蛋白质免疫共沉淀等方法，明确Ddx17在心肌损伤和心力衰竭发生中的作用并探讨其机制。本研究将从Ddx17这个新视点为揭示心肌细胞损伤的发生机制，为心力衰竭的防治提供新思路。

中文关键词： 心力衰竭；细胞凋亡；能量代谢；氧化应激；细胞信号转导

英文摘要： Cardiomyocyte injury is a major cause of heart failure. Transcription co-regulator play important role in regulating cardiomyocyte injury and heart failure. Ddx17 is a transcription co-regulator mainly expressed in cardiomyocyte. It is still not clear about the function of Ddx17 in caridomyocyte injury and heart failure. Our previous study found that Ddx17 was down regulated in heart failure patient and mouse with increased cardiomyocyte apoptosis. Overexpression of Ddx17 by adenovirus vector could decrease cardiomocyte oxidative stress and apoptosis. And we also found that Ddx17 could bind to NR3B1, and regulate NR3B1's function in cardiomyocyte. Thus, we hypothesize that Ddx17 could decrease cardiomyocyte injury and attenuate heart failure by regulating NR3B1 signal pathway. We will use gene transfer, RNA interference, immunohistochemistry and co-immunoprecipation to investigate Ddx17's role and its signal transduction pathways in molecular, cellular, tissular and animal levels during the development of heart failure. The study will reveal a new mechanism for Ddx17 function during cardiomyocyte injury and provide a new insight for the prevention and treatment of heart failure.

英文关键词： heart failure;cell apoptosis;energy metabolism;oxidative stress;cell signal transduction