心脏重构是多条信号通路相互作用、共同介导的结果。明确多条信号通路共同的下游分子及其调节机制对有效防治心脏重构至关重要。研究发现，乙酰化修饰在心脏重构发生中发挥关键调控作用。干扰素调节因子家族(Interferon regulatory factors,IRFs)是一类重要的多功能转录因子，乙酰化修饰是其发挥作用的重要调节方式。我们的前期研究发现，IRFs对于心脏重构具有重要调节作用，进一步研究发现心肌肥厚时IRF2，IRF7和IRF9乙酰化水平显著增加。然而，IRFs乙酰化修饰在心脏重构中的作用及机制尚不清楚。本项目结合前期工作，拟构建心脏重构细胞和动物模型，进一步明确心脏重构时IRF2，IRF7和IRF9的乙酰化位点，探寻其乙酰化修饰的乙酰转移酶/去乙酰化酶，阐明IRFs乙酰化修饰在心脏重构中的作用及分子机制。本项目将为深入理解心脏重构的机制提供新的理论依据，为防治心脏重构提供新靶点。

Cardiac remodeling involves multiple interacting signaling pathways. Thus, it is important to define downstream signaling mediators shared by several pathways and their regulatory mechanism. Recent studies suggest that acetylation modification plays critical role in the development of cardiac remodeling. Interferon regulatory factors (IRFs) are a family of important multifunctional transcriptional factors. Acetylation modification is an important regulatory mechanism by which IRFs exert their effects. Our preliminary studies indicated that IRFs play important role in cardiac remodeling. Furthermore, acetylation levels of IRF2, IRF7 and IRF9 were dramatically increased during cardiac hypertrophy. However, the role and the underlying mechanism of acetylation modification of IRFs in cardiac remodeling are unclear. Based on our preliminary results, we plan to identify the acetylation sites of IRF2, IRF7 and IRF9 during cardiac remodeling, to define the histone acetyltransferases/histone deacetylases modifying IRF2, IRF7 and IRF9, and to explore the role and molecular mechanism of IRFs acetylation modification in cardiac remodeling using in vitro and in vivo models. Successful completion of experiments outlined in this proposal will enhance our current understanding of the mechanism of cardiac remodeling, and may provide novel therapeutic strategies and targets for cardiac remodeling.