Exploration of the pathogenic mechanisms of inherited cardiomyopathies caused by cardiac troponin T mutations
| 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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Report
(3 results)
Research Products
(18 results)
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[Journal Article] SCH00013, a novel Ca^<2+> sensitizer with positive inotropic and no chronotropic action in heart failure.2005
Author(s)
Tadano, N., Morimoto, S., Yoshimura, A., Miura, M., Yoshioka, K., Sakato, M., Ohtsuki, I., Miwa, Y., Takahashi-Yanaga, F., Sasaguri, T.
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Journal Title
J.Phaimacol.Sci. 97
Pages: 53-60
NAID
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Conduction abnormality in gap junction protein connexin45-deficient embryonic stem cell-derived cardiac myocytes.2004
Author(s)
Egashira, K., Nishii, K., Nakamura, K., Kumai, M., Morimoto, S., Shibata, Y.
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Journal Title
Anat Rec. 280A(2)
Pages: 973-979
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Cardiac troponin T mutation R141W found in dilated cardiomyopathy stabilizes the troponin T-tropomyosin interaction and causes a Ca^<2+>-desensitization.2003
Author(s)
Lu, Q-W., Morimoto, S., Harada, K., Du, C-K., Takahashi-Yanaga, F., Miwa, Y., Sasaguri, T., Ohtsuld, I.
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Journal Title
J Mol.Cell.Cardiol. 35(12)
Pages: 1421-1427
Description
「研究成果報告書概要(欧文)」より
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[Book] モデル動物の作製と維持2004
Author(s)
原田 景太, 大田 美香, 森本 幸生
Total Pages
958
Publisher
(株)エル・エス・シー
Description
「研究成果報告書概要(和文)」より
Related Report
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