转化生长因子-β1诱导心脏成纤维细胞分化的DNA甲基化调控机制研究

项目名称： 转化生长因子-β1诱导心脏成纤维细胞分化的DNA甲基化调控机制研究

项目编号： No.81500204

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 潘啸东

作者单位： 东南大学

项目金额： 18万元

中文摘要： 心肌纤维化是多种心脏疾病发展到一定阶段的共同病理改变，其中心脏成纤维细胞分化是心肌纤维化进程中的关键环节。已有研究表明DNA甲基化修饰可影响基因表达，与肿瘤、组织纤维化等密切相关，然而在心脏成纤维细胞分化过程中的调控作用尚不明确。我们的前期研究工作发现转化生长因子-β1(TGF-β1)能通过抑制DNA甲基转移酶(DNMT)进而上调心脏成纤维细胞I型胶原基因表达，因此DNMT介导的DNA甲基化修饰方式很可能是心脏成纤维细胞分化的另一重要机制。本项目通过TGF-β1诱导心脏成纤维细胞分化，以DNMT1为切入点，运用转基因、RNA干扰、分子生物学及表观遗传学等技术，探讨TGF-β1调控DNMT1的分子机制，明确DNA甲基化修饰在心脏成纤维细胞分化中的调控作用。本项目将从表观遗传学角度为心脏成纤维细胞分化的机制上提供新的认识，而DNMT1则可作为新的治疗靶点为心肌纤维化防治研究提供新的思路。

中文关键词： 转化生长因子β1；心脏成纤维细胞分化；DNA甲基化；DNA甲基转移酶1

英文摘要： Myocardial fibrosis is of common pathological changes in various heart disease when develop to a certain stage and cardiac fibroblasts differentiation plays a key role in the process of myocardial fibrosis. Previous studies showed that DNA methylation affects gene expression and is closely related to the development of cancer and tissue fibrosis. However, regulation of cardiac fibroblasts differentiation by DNA Methylation is not yet clear. Our previous research found that transforming growth factor-β1 (TGF-β1) could downregulated the expression of DNA methyltransferases (DNMT) and upregulated the expression of Collagen I. DNMT-mediated DNA methylation modification is likely to be a new target for cardiac fibroblasts differentiation. In this project, rat cardiac fibroblasts differentiation will be induced by TGF-β1 and technologies such as genetically modified, RNA interference, molecular biology and epigenetic will be used. We will explore the regulation of TGF-β1 DNMT1 signal transduction mechanisms and clarify the regulation function of cardiac fibroblasts differentiation by DNA methylation. Our research will provide new insights in cardiac fibroblasts differentiation from the perspective of epigenetics and DNMT1 may be the new target for myocardial fibrosis prevention and treatment.

英文关键词： transforming growth factor-β1;cardiac fibroblasts differentiation;DNA methylation;DNMT1