染色质重塑复合物INO80在扩张型心肌病中的作用及其机制研究

Dilated Cardiomyopathy (DCM) is one of the most commonly occurring types of cardiomyopathies, with high morbidity and mortality. However, the mechanisms underlying DCM pathogenesis is incompletely understood. Emerging evidence point to a critical role of epigenetic regulation in DCM. Chromatin remodeling complex INO80 is a multi-subunit protein complex specialized in modulating chromatin architecture for the purpose of dynamic regulation of gene expression. Existing studies demonstrate that INO80 is crucial to establishing context-specific transcriptional programs in development and diseases. Our preliminary data show that the ATP-dependent core subunit Ino80 exhibits elevated expression in DCM patient myocardium compared to controls; and that Ino80 induces the expression of some DCM-associated genes. Therefore, we postulate that INO80 plays an important role in DCM pathogenesis. To test this hypothesis, we will first use neonatal rat cardiomyocytes to study the effect of Ino80 on the expression of DCM-related genes. Then, we will utilize cultured human cardiomyocytes to establish the relationship between INO80 and DCM. Finally, we will integrate multiple high-throughput sequencing techniques to depict the epigenetic mechanisms by which DCM-associated genes are regulated. This study will improve our understanding of the epigenetic regulatory mechanisms of DCM pathology, providing knowledge for the development of research and treatment strategies. Technique-wise, this work aims to surpass conventional models for studying DCM, in hopes of contributing to the establishment of a human cardiomyocyte research platform.

扩张型心肌病（DCM）是最常见的心肌病之一， 其发病机制尚未完全阐明。 近期多项研究提示基因的表观遗传调控在DCM中扮演重要角色 。染色质重塑复合物INO80是可以通过改变染色质结构而动态调节基因表达的大分子复合物。已有研究表明INO80在发育与疾病中建立特异的转录程序发挥着重要作用。我们预实验结果显示：该复合物核心亚基Ino80在DCM病人心肌高表达；Ino80过表达能激活部分DCM相关基因。因此，我们推测INO80在DCM发病过程中起关键作用。为验证该假设，拟首先在大鼠心肌细胞中研究INO80对DCM相关基因表达的影响；接着在人心肌细胞中验证INO80与DCM的关联性；最后拟通过多种高通量测序的方法获得DCM相关基因异常表达的表观遗传调控机制。本研究将从表观遗传学层面揭示DCM的病理机制，为其治疗策略的制定提供新的依据；在技术层面将突破传统研究模式，为建立人心肌细胞实验平台做出贡献。

心脏疾病是全球人类的头号杀手。深入了解对生活影响最为严重的一类心脏疾病之一，即心力衰竭（以下简称心衰），的疾病进程中细胞和分子的动态变化，是寻找新的治疗方法的关键所在。通过单细胞转录组测序，我们描绘了不同心功能状态的成人心脏：正常、心衰，以及心衰后部分恢复。我们发现一个高表达ACKR1的内皮细胞亚群维持心脏功能中起关键作用。心衰心脏中ACKR1高表达的内皮细胞数量显著减少。更为关键的是，将该群细胞注射至小鼠梗死心脏中可显著延缓心衰的发生发展，该方法可成为心肌梗死引发的心衰的潜在治疗手段。