| Project/Area Number |
16390219
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | 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) |
安波 道郎 東京医科歯科大学, 大学院・疾患生命科学研究部, 助教授 (80244127)
沢辺 元司 東京都老人医療センター, 剖検病理科, 医長 (30196331)
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| Project Period (FY) |
2004 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2006: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2005: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 2004: ¥5,100,000 (Direct Cost: ¥5,100,000)
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| Keywords | hypertrophic cardiomyopathy / dilated cardiomyopathy / mutation / pathogenesis / calcium sensitivity / stretch response / metabolic stress response / myosin light chain / 心不全 / 原因遺伝子 / 機能連関 / Z帯 / 遺伝子変異 / 高血圧性心筋症 / TCAP / 心筋リモデリング |
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| Research Abstract |
Heart failure is a disease condition defined by insufficient cardiac output required for oxygen supply. Causes of the most severe heart failure include hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). We have identified disease genes for HCM and/or DCM and suggested the linkage between the heart failure, and abnormality in Z-disc function. In this study, we aimed to identify the Z-disc abnormalities associated with heart failure and to reveal the molecular mechanisms of heart failure caused by the Z-disc abnormalities as well as to obtain a strategy to suppress the abnormal function of Z-disc. Main topics were as follows. (1) TCAP mutations were found in the patients with HCM and mutations in TCAP, CRYAB and FHL2 were, found in the patients with DCM. In addition MYPN mutation was found in restrictive cardiomyopathy, (RCM). TCAP, CRYAB, FHL2 and MYPN encoded components of Z-band or I-band, further supporting the pathological roles of abnormalities in the Z-I band function. (2) TTN mutations impaired interaction with FHL2 and CRYAB, suggesting the interaction of TTN with FHL2 and CRYAB was important for cardiac muscle function. (3) MYPN mutation found in RCM impaired formation of myofibrils in rat cardiomyocytes, suggesting the functional role of MYPN in cardiac sarcomerogenesis. (4) Cypher/ZASP bound to a metabolic enzyme and Cyper/ZASP mutations disrupted this interaction, and the metabolic enzyme was found to localized into Z-I band region upon stress to cardiomyocytes. These findings suggested a novel function of Z-band. (5) M21, a small inhibitory subunit of PP1M, increased calcium sensitivity of cardiac muscle contraction, and M21-overexpressing transgenic mice showed sudden death and cardiac hypertrophy accompanied by myocyte-disarrays, which were closely similar to the clinical observations in HCM. The M21-transgenic mice would be a good animal model for HCM and indicated that the increased calcium sensitivity was the cause of HCM.
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