CITED2在心脏干细胞衰老中的作用

项目名称： CITED2在心脏干细胞衰老中的作用

项目编号： No.31260285

项目类型： 地区科学基金项目

立项/批准年度： 2013

项目学科： 生物科学

项目作者： 周祖平

作者单位： 广西师范大学

项目金额： 56万元

中文摘要： 心脏干细胞（Cardiac stem cells，CSC）功能衰退是老年人群心脏病的主要内在原因之一。目前对CSC衰老的分子基础知之甚少。研究证明，CITED2是心脏发育和功能表现所必需的转录因子。CITED2敲除小鼠因心脏等器官发育缺陷而不能存活；CITED2基因突变则导致先天性心脏病。初步试验显示，CITED2在老龄小鼠CSC中的表达水平显著下降，实验性下调CSC的CITED2水平抑致细胞生长。基于这些证据，本项目拟探讨CITED2在心脏干细胞衰老中的作用；将开展三方面的工作：1）弄清CSC自我更新和分化潜能的年龄相关性变化规律；2）通过基因修饰技术确定CITED2对CSC功能的调节与机制；3）利用心肌梗死动物模型测定过表达CITED2对改善CSC心肌修复能力的效应。研究结果将提升对CSC衰老的行为变化及其调节机理的认识，并为发展年龄相关心脏疾病的CSC移植或在体介入处置策略奠定基础。

中文关键词： 心脏干细胞；增殖与分化；衰老；CITED 2；分子机制

英文摘要： The incidence and prevalence of cardiovascular diseases increase steeply with advancing age. Age-associated heart pathologies are thought to arise in part from degenerative changes in the organ's cellular compartment, primarily cardiac stem cells (CSCs). Currently, the molecular basis governing CSC aging remains unclear. Previous studies have demonstrated that CITED2, a transcription co-factor, is required for heart development and proper functioning. Mice deficient in CITED2 die at late gestation with cardiac malformation and other developmental defects. CITED2 mutations are found in patients with congenital heart disease. Our preliminary data indicate that CITED2 is strongly downregulated in aged CSCs, and its knockdown by shRNA cause cell growth arrest in vitro. Based on these findings, we propose to investigate the role of CITED2 in regulating CSC aging. To this end, the present project will focus on 1) addressing the age-dependent changes in the self-renewal capacity and differentiation potentials of mouse CSCs; 2) by utilizing gene modification techniques, determining the function of CITED2 in CSC maintenance with age and identifying mechanisms by which CITED2 modulates CSCs; 3) testing the ability of CITED2 to promote CSC-based repair of heart damage in vivo using a myocardial infarction animal model. The

英文关键词： Cardiac stem cells；Proliferation and differentiation；aging；CITED 2；Molecular mechanism