TBC1D7在心肌肥厚中的作用及其机制研究

项目名称： TBC1D7在心肌肥厚中的作用及其机制研究

项目编号： No.81470394

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 徐亚伟

作者单位： 同济大学

项目金额： 73万元

中文摘要： 心肌肥厚是一种复杂的动态过程，最终会导致心力衰竭。TBC1D7是TBC蛋白家族的成员，研究显示该蛋白可能通过mTORC调控疾病，但目前尚无TBC1D7对心肌肥厚作用的报道。本项目前期发现肥厚性心肌病该蛋白表达较正常心肌下降，而TBC1D7基因敲除小鼠在心肌肥厚的动物模型中明显加重心肌肥厚，并伴有心肌mTORC基因表达异常，提示TBC1D7蛋白可能通过mTORC参与心肌肥厚的发病机制。本项目拟通过构建 TBC1D7过表达和干扰腺病毒，分别感染原代心肌细胞，研究其对体外Ang II等诱导的心肌细胞肥大的作用。采用PCR、Western blot、免疫共沉淀等方法明确TBC1D7对心肌细胞作用的分子机制。另外构建 TBC1D7 基因敲除和转基因小鼠，观察不同基因型小鼠对心肌肥厚动物模型的作用及机制。以明确阐明 TBC1D7在心肌肥厚中的作用及其可能的分子机制，为心肌肥厚的防治提供新的分子靶点。

中文关键词： 心肌肥厚；心肌细胞；TBC1D7；转基因

英文摘要： Cardiac hypertrophy,a complex dynamic process,leads to heart failure ultimately. TBC1D7[(Tre-2/Bub2/Cdc16) domain family, member 7] is a member of TBC protein family.Researches have demonstrated this protein may regulate diseases via mTORC signaling. However,the role and mechanism of TBC1D7 in cardiac hypertrophy remains unclear.This project has discovered that TBC1D7 has a lower level in hypertrophic cardiomyopathy heart than in normal heart. The TBC1D7 knockout mice have more severe cardiac hypertrophy in transverse aortic constriction(TAC) induced cardiac hypertrophy mice, while the mTORC gene expression is also abnormal, which indicate that TBC1D7 may influence cardiac hypertrophy via mTORC signaling. This project will clarify the role and mechanism of TBC1D7 in cardiac hypertrophy at cell and animal level.The first part,We generate AdTBC1D7 and AdshTBC1D7 adenoviruses to infecte neonatal mice cardiomyocytes which are induced by Ang II to investigate the role and mechanism of TBC1D7 in cardiac hypertrophy at cell level.We will use PCR,Western blot and Co-Immunoprecipitation to find out the molecular mechanism of how TBC1D7 influence cardiac myocyte. The second part,we generate a TBC1D7 knock-out mouse model and a transgenic mouse model with cardiac-specific TBC1D7 expression to clarify the role and mechanism of TBC1D7 in cardiac hypertrophy at animal level. We try to clarify the role and mechanism of TBC1D7 in cardiac hypertrophy to provide new molecular target for prevention and therapy of cardiac hypertrophy.

英文关键词： cardiac hypertrophy;myocytes;TBC1D7;transgene