Exosome介导干细胞组蛋白甲基化调控心肌重构的研究

项目名称： Exosome介导干细胞组蛋白甲基化调控心肌重构的研究

项目编号： No.81330007

项目类型： 重点项目

立项/批准年度： 2014

项目学科： 医药、卫生

项目作者： 余细勇

作者单位： 广州医科大学

项目金额： 290万元

中文摘要： 心肌重构是心肌异常发育与损伤修复的共同病理生理学过程，与心脏干细胞的过早衰老密切相关，而后者受到病理性微环境的严重影响，但这一路径很少被关注。针对存在的问题，我们创新性提出研究思路：慢性缺血缺氧等危险因素作用于微环境的心肌细胞，分泌功能变异的Exosome，将非编码RNA等信使传递至分裂活跃的心脏干细胞，引发易感的组蛋白甲基化修饰改变，导致染色质重塑与心肌转录因子启动区的关闭，触发干细胞过早衰老或凋亡，丧失继续胚胎发育或者损伤修复的能力，发生心肌重构。本课题组继率先发现微环境能够“非细胞接触式”介导干细胞的心肌定向分化之后，再次深度挖掘微环境的核心传递物质Exosome的调控机制及其与心脏祖细胞（CPCs）的交互作用，从细胞水平和整体动物模型探讨病理性微环境所致CPCs组蛋白甲基化修饰与心肌重构的关系。研究结果不仅能揭示微环境作用的本质，而且能为心肌重构探寻出潜在的生物标志物或或干预靶点。

中文关键词： 组蛋白修饰;心肌重构;外泌体;组蛋白甲基化;心脏祖细胞

英文摘要： Myocardial remodeling is the common pathophysiological path of both myocardial abnormal development and myocardial damage repair, it closely related to the premature aging of cardiac stem cells which were easily attacked by pathologic niche. However, this path is rarely concerned about. Problems trigger innovative research ideas: under the stimulation of risk factors, such as chronic ischemia and hypoxia, the myocardial cells in the microenvironment will secrete variation exosome that transfer some non-coding RNA (ncRNAs) to the susceptible cardiac stem cells; then ncRNAs triggered histone methylation of stem cells, methylation modification will change chromatin structure and close the promoter region of cardiac transcription factors; finally, the stopped transcription will trigger the premature senescence or apoptosis, stem cells lose their continue ability of embryonic development or wound repair capacity, the myocardial remodeling inevitably occurs. This project will focus on above new ideas to carry out a series of studies. Following the first discovery that myocardial differentiation of stem cell was mediated by “non-cell-contact” niche, our research group, once again explores the regulation mechanism of exosome, an key message of microenvironment, and its cross-talks with cardiac progenitor cells (CPCs). The research will be carried out from cellular levels to whole animal models, try to find out the relationship between the myocardial remodeling and CPCs histone methylation caused by pathogenic factors. We can expect that the results not only reveal how does signaling transduction by the niche, but also explore the potential biomarkers or intervention targets of myocardial remodeling.

英文关键词： Histone modification;Myocardial remodeling;Exosome;Histone methylation;Cardiac Progenitor cell