Molecular Pathogenesis of Cardiac Failure due to Gene Abnormalities

基因异常导致心力衰竭的分子发病机制

基本信息

批准号：
13470142
负责人：
KIMURA Akinori
金额：
$ 6.27万
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：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

Idiopathic cardiomyopathy was defined as cardiomyopathy of unknown etiology. Recent molecular genetic analysis has revealed that gene abnormalities are involved in the etiology and/or pathogenesis of idiopathic cardiomyopathy. As well, hypertensive cardiomyopathy may also be relevant to the gene abnormalities in the pathogenesis. In this study, we have revealed that mutations in the genes for Z-disk elements, TTN, TCAP, MLP, and Cypher, cause cardiomyopathy. Functional studies of the mutations in each disease gene have shown that hypertrophic cardiomyopathy-related mutations increase the binding ability of the Z-disk elements, whereas dilated cardiomyopathy-related mutations decrease the binding ability. It also has been demonstrated that the Z-disk plays a key role in the stretch-sensing of cardiomyocytes from the analysis of a well known dilated cardiomyopathy model of MLP deficient mice. It was suggested that the stretch-response involved phosphorylation of Z-disk proteins, because the Z-disk protein abnormalities were predicted to change the distribution of calcineurin and PKC. In addition, Ca-sensitization and -desensitization played a crucial role in the pathogenesis of cardiac hypertrophy and failure, respectively. Analysis of hypertrophied and dilated hearts from M21-transgenic mice and Dah1 salt-sensitive hypertensive rats by DNA-chip technology showed that a number of genes were involved in the pathogenesis of cardiomyopathy. One of the new genes identified to be differentially expressed in the cardiac hypertrophy and failure is a growth factor-like gene specifically expressed in the heart. We identified a mutation in that growth factor-like gene that was associated with hypertensive cardiomyopathy.

特发性心肌病被定义为病因不明的心肌病。最近的分子遗传学分析表明，基因异常与特发性心肌病的病因和/或发病机制有关。此外，高血压心肌病的发病也可能与基因异常有关。在这项研究中，我们发现 Z 盘元件 TTN、TCAP、MLP 和 Cypher 基因的突变会导致心肌病。对每个疾病基因突变的功能研究表明，肥厚型心肌病相关突变增加了Z盘元件的结合能力，而扩张型心肌病相关突变降低了结合能力。通过对众所周知的 MLP 缺陷小鼠扩张型心肌病模型的分析，还证明 Z 盘在心肌细胞的拉伸感知中发挥着关键作用。有人认为拉伸反应涉及 Z 盘蛋白的磷酸化，因为 Z 盘蛋白异常预计会改变钙调神经磷酸酶和 PKC 的分布。此外，Ca2+敏化和Ca2+脱敏分别在心脏肥大和衰竭的发病机制中发挥着至关重要的作用。通过DNA芯片技术对M21转基因小鼠和Dah1盐敏感性高血压大鼠的肥大和扩张的心脏进行分析表明，许多基因参与了心肌病的发病机制。确定在心脏肥大和衰竭中差异表达的新基因之一是在心脏中特异性表达的生长因子样基因。我们发现了与高血压心肌病相关的生长因子样基因的突变。

项目成果

期刊论文数量（64）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Knoll R, Hoshijima M, Hoffmann HM, Person V, Lorenzen-Schmidt I, Bang M-L, Hayashi T, Shiga N, Yasukawa H, Schaper W, McKenna W, Yokoyama M, Schork J, Jeffrey H, Omens J, Andrew D, McCulloch A, Kimura A, Gregorio CC, Poller W, Schaper J, Schultheless HP,

Knoll R、Hoshijima M、Hoffmann HM、Person V、Lorenzen-Schmidt I、Bang M-L、Hayashi T、Shiga N、Yasukawa H、Schaper W、McKenna W、Yokoyama M、Schork J、Jeffrey H、Omens J、Andrew D、