| Project/Area Number |
15300136
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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 |
Neurophysiology and muscle physiology
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
MORIMOTO Sachio Kyushu University, Graduate School of Medicine, Associate Professor, 大学院・医学研究院, 助教授 (50202362)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2004: ¥7,900,000 (Direct Cost: ¥7,900,000)
Fiscal Year 2003: ¥6,800,000 (Direct Cost: ¥6,800,000)
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| Keywords | Dilated cardiomyopathy / Hypertrophic cardiomyopathy / Ristrected cardiomyopathy / Troponin / Gene mutation / Knock-in mouse / Calcium sensitivity / Mouse model for human diseases / 遺伝子突然変異 / 心筋症 / 遺伝子改変 / モデル動物 / ノックアウトマウス / サルコメア病 |
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| Research Abstract |
Dilated cardiomyopathy (DCM) represents a heterogeneous group of inherited and acquired disorders characterized by cardiac dilation and systolic dysfunction, which leads to heart failure and sudden death, being the primary indication for cardiac transplantation. DCM-causing mutations have been found in the genes for cytoskeletal and sarcomeric proteins. We have created a knock-in mouse model for DCM caused by the deletion mutation ΔK210 in cardiac troponin T. Mutant mice developed enlarged hearts and showed a high incidence of sudden death with no sign of heart failure. Histological examination of cardiac sections from mutant mice showed a significant dilation of both ventricles with mild to moderate fibrosis. Echocardiography measurements showed that the ejection fraction of left ventricle was significantly smaller in mutant mice than in wild-type mice, indicating a reduced systolic function of mutant mice hearts in vivo. Isolated working heart preparations from mutant mice showed a decreased dP/dt_<max> with no significant change in dP/dt_<min>. However, no significant reduction in cardiac output was found in mutant mice, suggesting a complete compensation by ventricular enlargement. Studies using a telemetry system for ECG recording strongly suggested that the deletion mutation ΔK210 in cardiac troponin T results in a high incidence of sudden death due to a cardiac electrophysiological abnormality despite well-compensated mechanical performance of the heart.
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