项目名称： PKR在心力衰竭中的作用机制研究

项目编号： No.81470512

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： 陈英杰

作者单位： 同济大学

项目金额： 73万元

中文摘要： 我们课题组长期致力于充血性心力衰竭（CHF）致病分子机制研究，目前重点聚焦在探索mRNA翻译起始调控CHF发病的作用。前期研究发现通过4EBP1、PKR及GCN2基因敲除增加mRNA翻译起始可以显著改善高压力负荷诱导的CHF。然而PKR导致心力衰竭的分子机制以及是否可以利用PKR抑制剂治疗CHF尚不完全清楚。本课题拟从动物、细胞及分子水平，在以下4个方面系统阐述PKR在心力衰竭中的重要作用：①确定心肌细胞PKR在CHF中的作用；②探索PKR过表达与CHF发病的因果关系；③研究PKR抑制剂治疗CHF的作用；④阐述PKR调控心力衰竭的分子机制。本研究将系统阐明PKR在心力衰竭中的作用机制，为心力衰竭的防治提供新的分子靶点。

中文关键词： PKR；心力衰竭；压力超负荷；翻译调控

英文摘要： Our laboratory investigates mechanisms of congestive heart failure (CHF) development, focusing on translation initiation. We recently observed that enhancing cap-dependent mRNA translation initiation by gene deletion of 4EBP1, PKR or GCN2 protects the heart against TAC-induced CHF with minimal impact to LV hypertrophy. Based on our findings that PKR KO provides robust cardiac protection against CHF development, and the fact that PKR inhibitors are available, we hypothesize that PKR may be important novel therapeutic targets for treating CHF. Therefore, the central aim of this project is to determine the underlying molecular mechanisms by which PKR exacerbates TAC-induced CHF, and explore the therapeutic potential of inhibiting activity of this translation repressor as treatment for CHF. We will pursue the following major research objectives: (1) Determine the effect of cardiac specific PKR on CHF; (2) Determine the effect of PKR over expression on CHF development. Our working hypothesis is that increase of PKR activity causes or exacerbates TAC-induced CHF; (3) Determine the consequences of PKR inhibition by PKR KO and pharmacological PKR inhibitors on TAC-induced CHF and reversal of established CHF. Our working hypothesis is that attenuating PKR activity will protect the heart from TAC-induced CHF; (4) Determine the molecular mechanism(s) by which PKR impairs the cardiac adaptation to stress. Our proposed studies will provide novel insights into how changes in translational initiation influence CHF development, and will explore the therapeutic potential of PKR inhibition as a treatment for CHF.

英文关键词： PKR;heart failure;pressure overload;translational regulation