心脏病理性重构过程中表型基因程序转换的表观遗传调控新机制研究

心力衰竭是多数心血管疾病的最终临床转归，防止和延缓心脏病理性重构是治疗的关键和瓶颈之一。在重构过程中，与心肌收缩相关的蛋白由成人表型转为胎儿表型，这种转变不利于心肌对ATP的利用，无法满足心肌收缩的生理需求。我们前期成功建立了胎儿心力衰竭大鼠模型，在此基础上发现胎儿期与成年期心力衰竭表型蛋白相关基因程序出现差异性表达，成人表型蛋白水平与心脏功能正相关，并证实SWI/SNF与YY-1/HDAC复合物参与该差异性表达的调控；利用HDAC穿梭机制，在胎儿期可以实现对胎儿/成年基因程序的调控。由此，本项目拟通过系统研究不同时期SWI/SNF及YY-1/HDAC复合物的表达特点、组成结构、募集特征及调控方向，建立SWI/SNF及YY-1/HDAC复合物交互协同作用网络，揭示心脏病理性重构时胎儿基因程序/成年基因程序开启或关闭的表观遗传调控机制，筛选潜在干预靶点，为心力衰竭的防治提供全新的思路。

Heart failure is the end stage of most cardiovascular diseases. The key issue for the treatment of heart failure is prevention of pathological cardiac remodeling. The aberrant transformation of cardiac contractile proteins from adult phenotypes to fetal phenotypes has been implicated in the remodeling process, which leads to the impairment of ATP metabolism in myocardial cell, disrupting the energy homeostasis in myocardial contraction. Our previous study based on our pioneer fetal heart failure rat model, revealed a transformation from fetal phenotypes to adult phenotypes in fetal myocardial cells on the basic of a heart failure model in embryonic rats. Besides regression analysis demonstrated the expression of adult phenotypes were directly correlated with cardiac function. We also showed that SWI/SNF chromatin remodeling complex and transcription factor YY-1 with several HDACs were involved in this process, and made use the shutting mechanism of HDAC to realize the regulation of fetal and adult gene program in fetal period. In this project, we will study the expression, structure, recruitment and regulation characteristics of SWI/SNF and YY-1/HDAC complex in different periods to build the interaction network. Moreover, we will reveal the regulation mechanism of fetal and adult gene program during pathological cardiac remodeling and identify the potential the therapeutic targets. Our research will benefit the elucidation of the epigenetic regulation mechanism underlying pathological cardiac remodeling, providing insights into the prevention and treatment of heart failure.