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

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470142/
• 关键词: Gene; Cardiac Failure; Cardimyopathy; Stretch Response; Z-disk; Hypertension; Polymorphism; Mutation; 肥大型心筋症; 拡張型心筋症; Cypher変異; PKC; カルサルチン; Tcap; カベオリン; 遺伝子変異; トランスジェニックマウス; タイチン; MLP; ミオシン脱リン酸化; 心肥大; テレトニン

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未知病因的心肌病。最近的分子遗传分析表明，基因异常与特发性心肌病的病因和/或发病机理有关。同样，高血压心肌病也可能与发病机理中的基因异常有关。在这项研究中，我们揭示了Z磁盘元素TTN，TCAP，MLP和Cypher的突变引起心肌病。每个疾病基因突变的功能研究表明，肥厚性心肌病相关的突变会增加Z磁盘元素的结合能力，而扩张的心肌病变相关的突变则降低了结合能力。还已经证明，Z磁盘在对MLP缺乏小鼠的众所周知的扩张心肌病模型的分析中通过分析心肌细胞的拉伸感应起关键作用。有人提出，拉伸响应涉及Z二烟蛋白的磷酸化，因为预计Z-二烟蛋白异常会改变钙调蛋白和PKC的分布。此外，CA-敏化和 - 敏化分别在心脏肥大和衰竭的发病机理中起着至关重要的作用。通过DNA-CHIP技术对M21-转基因小鼠和DAH1盐敏感大鼠的肥大和扩张心脏的分析表明，许多基因参与心肌病的发病机理。在心脏肥大中鉴定出差异表达的新基因之一，失败是一种特异性在心脏中表达的生长因子样基因。我们确定了与高血压心肌病有关的类似生长因子样基因的突变。

项目成果

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、

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