LMNA截断突变诱发扩张型心肌病的作用机制研究

Dilated cardiomyopathy is a major cardiovascular diseases to human health nowadays. So far, the following mutated genes have been identified such as nuclear membrane associated genes, among these mutant genes, the LMNA gene has the most diverse number of mutations. However, the mechanism of dilated cardiomyopathy induced by LMNA mutations remains unclear recently. According to our previous studies, we will focus on how the LMNA mutations regulate the cell structure and function and associated pathway in myocardial in this project, following work will be performed 1) study on the effects of LMNA truncation mutation on myoblasts physiological characteristics and function of myoblast; 2) work on how LMNA truncating mutations affect structure of the nuclear membrane, distributions of lamins and protein partaners and the intracting ability with binding proteins; 3) analysis LMNA truncating mutations how to regulate the key signaling molecules associated with myocardial occurrence and functions; 4) study on the effect of LMNA truncation mutations on the differentiation of cardiac stem cells. The project results will improve the our understanding on the molecular basis of dilated cardiomyopathy induced by LMNA mutations, and provide a theoretical and technical foundation for the development of new clinical therapeutic strategies.

扩张型心肌病属于危害人类健康的重大疾病，核膜蛋白尤其是核纤层蛋白基因LMNA突变是主要的遗传易感因素之一引发心肌病变，迄今为止已确定的突变基因以核膜蛋白为最多。但是，目前对LMNA诱发扩张型心肌病的确切分子机制仍不清楚。基于我们先前的研究，本项目旨在探讨LMNA突变在调节心肌细胞结构与功能中的作用与途径，具体研究工作包括1）测定LMNA截断突变对成肌细胞生理特性和功能的影响；2）测定LMNA截断突变对核膜结构、核纤层蛋白及其结合蛋白胞内分布与定位和结合能力的影响；3）分析LMNA截断突变对心肌发生与功能相关重要信号分子表达的影响；4）分析LMNA截断突变对心脏干细胞分化的影响。项目研究结果将增进人们对LMNA突变诱发扩张型心肌病的分子基础的认识与理解，并为发展相关新型临床治疗策略奠定理论与技术基础。

扩张型心肌病属于危害人类健康的重大疾病，核膜蛋白尤其是核纤层蛋白基因LMNA突变是主要的遗传易感因素之一引发心肌病变，迄今为止已确定的突变基因以核膜蛋白为最多。但是，目前对LMNA诱发扩张型心肌病的确切分子机制仍不清楚。基于我们先前的研究，本项目旨在探讨LMNA突变在调节心肌细胞结构与功能中的作用与途径,具体研究工作和相关结果如下1）构建扩张型心肌病相关的LMNA突变；进而确定扩张型心肌病密关联LMNA突变对细胞结构与功能的调节的潜在作用途径；3）最后我们还进一步鉴定扩张型心肌病密关联LMNA突变发挥作用的关键互作蛋白与信号转导通路。项目研究结果将增进人们对LMNA突变诱发扩张型心肌病的分子基础的认识与理解，并为发展相关新型临床治疗策略奠定理论与技术基础。