Development of strategies for handling heart failure based on the molecular pathogenesis of cardiomyopathy

基于心肌病的分子发病机制制定治疗心力衰竭的策略

基本信息

批准号：
22390157
负责人：
KIMURA Akinori
金额：
$ 11.9万
依托单位：
Tokyo Medical and Dental University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2012
项目状态：
已结题

项目摘要

Identification of novel disease genes for cardiomyopathy and functional analyses of various cardiomyopathy-associated mutations were performed. We identified novel disease genes for cardiomyopathy, such that CARP mutations in hypertrophic cardiomyopathy, nebulette mutations and BAG3 in dilated cardiomyopathy,and myopalladin mutations in hypertrophic cardiomyopathy, dilated cardiomyopathy and restrictive cardiomyopathy. Functional studies of the cardiomyopathy-associated mutations revealed that CARP mutations increased binding to titin and enhance the nuclear translocation. Nebulette mutations impaired sarcomerogenesis and BAG3 mutations increased susceptibility to stress-induced apoptosis. Myopalladin mutations impaired sarcomerogenesis. In addition, we revealed a molecular mechanism for calcium sensitivity of cardiac contraction by heart-specific small subunit of myosin phosphatase, M21.Moreover, it was demonstrated that a chemical enhancing calcium sensitivity of muscle contraction, SCH00013, could prolong the survival prognosis of dilated cardiomyopathy in lamina/C mutation knock-in mice, suggesting that the regulation of calcium sensitivity is a novel therapeutic/preventive strategy for heart failure associated with cardiomyopathy

对心肌病的新型疾病基因的鉴定以及各种心肌病相关突变的功能分析。我们确定了心肌病的新型疾病基因，从而使肥厚性心肌病中的鲤鱼突变，烟囱突变和BAG3在扩张的心肌病中和肥大性心肌病中的肌无甲麦素突变，心肌病的扩张和限制性心肌病。心肌病相关突变的功能研究表明，鲤鱼突变增加了与钛的结合并增强了核易位。烟雾结构性和BAG3突变障碍突变会增加对压力诱导的凋亡的敏感性。肌动蛋白突变损害肉瘤发生。 In addition, we revealed a molecular mechanism for calcium sensitivity of cardiac contraction by heart-specific small subunit of myosin phosphatase, M21.Moreover, it was demonstrated that a chemical enhancing calcium sensitivity of muscle contraction, SCH00013, could prolong the survival prognosis of dilated cardiomyopathy in lamina/C mutation knock-in mice, suggesting that the regulation of calcium sensitivity is a与心肌病有关的新型治疗/预防性策略

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A frameshift deletion mutation in the cardiac myosin-binding protein C gene was associated with dilated phase of hypertrophic cardiomyopathy and dilated cardiomyopathy

心肌肌球蛋白结合蛋白C基因的移码缺失突变与肥厚型心肌病和扩张型心肌病的扩张期相关

DOI：
发表时间：
2010
期刊：
J Cardiol
影响因子：
2.5
作者：
Hitomi N;Kubo T;Kitaoka H;Hirota T,Hamada T;Hoshikawa E;Hayato K;Okawa M;Kimura A;Doi YL
通讯作者：
Doi YL

A novel mechanism of Brugada syndrome:Mutation of sarcolemmal membrane-associated protein (SLMAP) gene impaired hNav1.5 function

Brugada综合征的新机制：肌膜相关蛋白（SLMAP）基因突变损害hNav1.5功能

DOI：
发表时间：
2012
期刊：
影响因子：
0
作者：
Ishikawa T;Sato A;Arimura T;Sakurada H;Makita N;Kimura A
通讯作者：
Kimura A

Novel molecular mechanisms of idiopathic cardiomyopathy

特发性心肌病的新分子机制

DOI：
发表时间：
2011
期刊：
影响因子：
0
作者：
Arimura T;Kimura A
通讯作者：
Kimura A

Loss-of-function of hNav1.5 by ZASP1-D117N associated with intraventricular conduction disturbances in left ventricular noncompaction

ZASP1-D117N 导致的 hNav1.5 功能丧失与左心室致密化不全的室内传导障碍相关

DOI：
发表时间：
2012
期刊：
Circ Arrhythm Electrophysiol
影响因子：
0
作者：
Xi Y;Ai T;De Lange E;Li Z;Wu G;Brunelli L;Kyle WB;Cheng J;Ackerman MJ;Kimura A;Weiss JN;Qu Z;Kim JJ;Faulkner G;Vatta M
通讯作者：
Vatta M

Novel SCN3B Mutation Associated With Brugada Syndrome Affects Intracellular Trafficking and Function of Nav1.5