权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Cardio-Specific Gene Expression and Genetic Analysis of Myocardial Disorders

心脏特异性基因表达和心肌疾病的遗传分析

基本信息

批准号：
05304032
负责人：
YAZAKI Yoshio
金额：
$ 11.2万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Co-operative Research (A)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-05304032/
关键词：
cardio-specific gene expression cardiac hypertrophy mechanism of transcriptional regulation homeobox gene hypertvophic cardiomyopathy mitochondrial cardiomyopathy dilated cardiomyopathy long QT syndrome 心筋細胞遺伝子発現心不全心筋症 BNP カリウ

项目摘要

(A) Mechanisms of Cardio-Specific Regulation of the Genes Important to cardiac FunctionsAs for the mechanisms of cardiac hypertrophy, we showed using an in vitro stretch-model of cultured cardiac myocytes that the intracellular signaling cascades involving MAP kinase is, at least in part, mediated by myocardial angiotensin II and that myocardial renin-angiotensin system causes hypertrophy of cardiac myocytes and interstitial fibrosis. We also clarified the mechanisms regulating the expression and transcription of cardiac genes such as cytokine (IL-6), hormones (ANP,BNP,renin, angiotensin), potassium channel, and calcium pump in response to ischemia, mechanical load, calcium, and thyroid hormone. Furthermore, we isolated the human Csx gene using the murine Csx (cardio-specific homeobox) gene as a probe and found that the amino acid sequences of human and murine Csx genes are very similar, indicating that Csx gene is highly conserved among the species.(B) Analysis of the Genes Responsible for Myocardial DisordersFourteen missense mutations of the cardiac beta-myosin heavy chain gene were detected in Japanese patients with hypertrophic cardiomyopathy (HCM), and 13 out of these 14 mutations were different from those found in Caucasian patients. In 11 out of 47 affected Japanese families, there was no linkage to cardiac beta-myosin heavy chain gene, indicating the genetic heterogeneity of Japanese patients with HCM.We also identified a point mutation in tRNA-Leu gene and deletions of mitochondrial DNA in patients with mitochondrial cardiomyopathy who had cardic hypertrophy. Furthermore, we found linkage of Japanese dilated cardiomyopathy to HLA-DR locus, and Japanese long QT syndrome (Romano-Ward syndrome) to HRAS and D11S922 loci on chromosome 11p15.5.

(A)心脏功能重要基因的特异性调节机制对于心肌肥大的机制，我们使用体外培养心肌细胞的牵张模型表明，涉及MAP激酶的细胞内信号级联至少部分由心肌血管紧张素II介导，心肌肾素-血管紧张素系统导致心肌细胞肥大和间质纤维化。我们还阐明了调节心脏基因的表达和转录的机制，如细胞因子（IL-6），激素（ANP，BNP，肾素，血管紧张素），钾通道和钙泵响应缺血，机械负荷，钙和甲状腺激素。此外，我们用小鼠Csx基因作为探针分离了人Csx基因，发现人和小鼠Csx基因的氨基酸序列非常相似，表明Csx基因在物种间高度保守。(B)心肌疾病相关基因的分析在日本肥厚型心肌病（HCM）患者中检测到14种心肌β-肌球蛋白重链基因的错义突变，其中13种与高加索人不同。在47个日本HCM家系中，有11个家系与心肌β-肌球蛋白重链基因无连锁关系，表明日本HCM患者存在遗传异质性。我们还发现了心肌肥厚的线粒体心肌病患者的tRNA-Leu基因点突变和线粒体DNA缺失。此外，我们发现日本扩张型心肌病与HLA-DR位点连锁，日本长QT综合征（Romano-Ward综合征）与染色体11p15.5上的HRAS和D11 S922位点连锁。