| Project/Area Number |
12204004
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Medical Research Institute, Tokyo Medical and Dental University |
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Principal Investigator |
KIMURA Akinori Tokyo Medical and Dental University, Medical Research Institute, Professor, 難治疾患研究所, 教授 (60161551)
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| Co-Investigator(Kenkyū-buntansha) |
IZUMI Toru Kitasato University, Faculty of Medicine, Professor, 医学部, 教授 (80143775)
YASUAMI Michio Tokyo Medical University, School of Biomedical Sciences, Associated Professor, 大学院疾患生命科学研究部, 助教授 (80244127)
赤井 潤 東京医科歯科大学, 難治疾患研究所, 助手 (70302891)
吉田 雅幸 東京医科歯科大学, 難治疾患研究所, 助教授 (80282771)
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| Project Period (FY) |
2000 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥59,900,000 (Direct Cost: ¥59,900,000)
Fiscal Year 2004: ¥16,000,000 (Direct Cost: ¥16,000,000)
Fiscal Year 2003: ¥16,000,000 (Direct Cost: ¥16,000,000)
Fiscal Year 2002: ¥14,400,000 (Direct Cost: ¥14,400,000)
Fiscal Year 2001: ¥13,500,000 (Direct Cost: ¥13,500,000)
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| Keywords | 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 |
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| Research Abstract |
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
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