LRRC10在扩张性心肌病中的调控机制

扩张型心肌病（扩心病）严重威胁着人类健康，其病因不明。LRRC10基因在人类扩心病家系中存在点突变，申请人与国际同行均发现小鼠中敲除Lrrc10导致自发性心脏扩张，但其分子信号调控机制未知。申请人早期通过酵母双杂交鉴定出其互作蛋白SRF，且与扩心病有关的骨架蛋白和收缩蛋白是SRF的直接靶基因。据此，申请人假设：LRRC10-SRF信号轴调控扩心病发生。此机制目前国际上尚无报道。在本项目中，申请人拟利用小鼠敲除模型结合体内外点突变心肌细胞模型，研究三个问题：1）SRF是否介导LRRC10调控小鼠扩张型心肌病的发生？2）人类LRRC10点突变是否通过影响LRRC10-SRF作用机制而导致扩张型心肌病的发生？3）LRRC10在疾病人群当中的基因突变谱是什么？以阐明LRRC10-SRF信号轴在人类扩心病发生过程中的调控机制，为临床诊断和干预扩心病提供理论线索。

Dilated cardiomyopathy (DCM) is a serious threat to human health，but the etiology remains unknow, LRRC10 point mutations were identified in families with DCM. Our previous study and international counterparts demonstrated LRRC10 deletion in mice caused spontaneous heart expansion, but the underlying mechanism was unclear. Using the yeast two-hybrid strategy, we previously identified an interaction protein SRF, which known as directly targeting skeletal protein and contractile protein associated with DCM. We thus assume that the LRRC10-SRF signal axis regulates the occurrence of DCM, which no reported in the world. In this study, Using the gene knockout mice and in vitro / vivo point mutation knock in cardiomyocyte models, we intend to explore three questions: 1) Does SRF mediate LRRC10 regulation of DCM in mice? 2) Does human LRRC10 point mutation lead to the development of DCM by affecting the mechanism of LRRC10-SRF signal axis? 3) What is the genetic mutation spectrum of LRRC10 among the disease population? In order to clarify the regulation mechanism of LRRC10-SRF signal axis in the process of human DCM, provide theoretical clues for clinical diagnosis and intervention for DCM.