Identification of Disease-associated Genes for Cardiovascular Diseases

心血管疾病相关基因的鉴定

• 批准号: 12204004
• 负责人: KIMURA Akinori
• 金额: $ 38.34万
• 依托单位: Medical Research Institute, Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12204004/
• 关键词: gene mutation; hypertensive cardiomyopathy; arrhythmia; heart failure; myocardial infarction; microsatellite; Intractable arteritis; idiopathic cardiomyopathy; ゲノム多様性; LTA; 高血圧; 心筋症; 高安病; 動物モデル; HLA; 心肥大; 循環器疾患; 機能解析; DSSラット

Myocardial infarction: We found significant associations of myocardial infarction with polymorphisms in SELE, PECAM1 and CD14. It also was revealed that the disease-associated SELE allele lead higher binding between leukocytes and vascular endothelial cells. In contrast no association was found for the reported polymorphisms in LTA, LGALS2 and p22phox genes via the analysis of more than 500 patients and 500 controls. On the other hand, we could identify five novel disease-related loci for myocardial infarction via the analysis of 18,800 microsatellite markers.Cardiomyopathy: Gene-Chip analysis of hypertrophied hearts and failing hearts from Dahl salt-sensitive hypertensive rats enabled us to identify 258 genes showing increased or decreased expression in association with hypertensive cardiomyopathy. By analyzing human orthologues of these genes we identified a BMP10 variant associated with hypertensive dilated cardiomyopathy. Biochemical and cell biological analyses revealed that BMP10 … More localized in Z-disc and bound Tcap. The BMP10 variant reduced the binding to Tcap and augmented extracellular secretion of BMP10. In addition, candidate gene approaches have revealed two novel disease genes for hypertrophic cardiomyopathy and four disease genes for dilated cardiomyopathy.Arrhythmia: In this study, we have identified many disease-associated mutations in cardiac channel genes and revealed functional changes caused by the mutations. In addition, an HCN4 mutation was revealed to be a novel disease gene for ventricular arrhythmia since a disease-linked mutation showed dominant loss-of-function of HCN4 channel.Vasculitis: We have investigated polymorphisms of microsatellite markers and SNPs in the HLA region in patients with Takayasu arteritis or Buerger disease. It was revealed that there were two disease-associated loci for Takayasu arteritis; one was HLA-B and the other was mapped in TNF-MICA region. In contrast, there were at least three disease-associated loci for Buerger disease; first was HLA-DPB1, second was HLA-DRB1, and third was mapped near the HLA-E gene. Less

心肌梗死：我们发现心肌梗死与SELE、PECAM 1和CD 14的多态性显著相关。研究还表明，疾病相关的SELE等位基因导致白细胞与血管内皮细胞之间的结合更高。相反，通过对500多名患者和500名对照的分析，未发现LTA、LGALS 2和p22 phox基因的多态性与此相关。另一方面，我们可以通过分析18，800个微卫星标记物来确定5个新的与心肌梗死相关的疾病位点。心肌病：基因芯片分析Dahl盐敏感性高血压大鼠的肥厚心脏和衰竭心脏，使我们能够确定258个与高血压性心肌病相关的表达增加或减少的基因。通过分析这些基因的人类直向同源物，我们确定了与高血压扩张型心肌病相关的BMP 10变体。生物化学和细胞生物学分析表明，BMP 10 ...更多信息 定位于Z盘和结合Tcap。BMP 10变体减少了与Tcap的结合并增强了BMP 10的细胞外分泌。此外，候选基因的方法已经揭示了两个新的疾病基因肥厚型心肌病和四个疾病基因扩张型cardiomyosis.Arrhythmia：在这项研究中，我们已经确定了许多疾病相关的突变，心脏通道基因，并揭示了功能的变化所造成的突变。此外，HCN 4突变被发现是一种新的疾病基因室性心律失常，因为疾病相关的突变表现出显性损失的功能HCN 4 channel.Vasculitis：我们已经调查了微卫星标记和单核苷酸多态性在HLA区域的患者与大动脉炎或Buerger病。结果表明，大动脉炎有两个疾病相关位点，一个是HLA-B，另一个定位在TNF-MICA区域。与此相反，有至少三个疾病相关的基因座为伯格病;第一个是HLA-DPB 1，第二个是HLA-DRB 1，第三个是定位在HLA-E基因附近。少

项目成果

Unexpected mexiletine responses of a mutant cardiac Na+ channel implicate the selectivity filter as a structural determinant of antiarrhythmic drug access

• DOI: 10.1124/mol.66.2.330
• 发表时间: 2004-08-01
• 期刊: MOLECULAR PHARMACOLOGY
• 影响因子: 3.6
• 作者: Sasaki, K;Makita, N;Kitabatake, A
• 通讯作者: Kitabatake, A

Itoh-Satoh M, Hayashi T, Nishi H, et al.: "Titin mutations as the molecular basis for dilated cardiomyopathy."Biochem. Biophys. Res. Commun.. 291. 385-393 (2002)

Itoh-Satoh M、Hayashi T、Nishi H 等人：“Titin 突变是扩张型心肌病的分子基础。”Biochem。

Kimura A, et al.: "Frontiers in Cardiovascular Health (eds. Dhalla NS, et al.)"Klumer Academic Publishers, Boston(印刷中).

Kimura A 等人：“心血管健康前沿（Dhalla NS 等人编辑）”Klumer 学术出版社，波士顿（正在印刷中）。

Identification of IkBL as the second MHC-linked susceptibility locus for Rheumatoid Arthritis

鉴定 IkBL 作为类风湿性关节炎的第二个 MHC 相关易感位点

• 发表时间: 2003
• 期刊: Am J Hum Genet 72
• 作者: Okamoto K;Makino S;Yoshikawa Y;Takaki A;Nagatsuka Y;Ota M;Tamiya G;Kimura A;Bahram S;Inoko H
• 通讯作者: Inoko H

Identification of MICA alleles with a long Leu-repeat in the transmembrane region and no cytoplasmic tail due to a frameshift deletion in exon 4.

鉴定在跨膜区域具有长 Leu 重复序列且由于外显子 4 中移码缺失而没有胞质尾部的 MICA 等位基因。

• 发表时间: 2001
• 期刊: Tissue Antigens 57
• 作者: Obuchi N;Takahashi M;Nouchi T;Satoh M;Arimura T;Ueda K;Akai J;Ota M;Naruse T;Inoko H;Numano F;Kimura A
• 通讯作者: Kimura A