New therapeutic approach for heart failure using HB-EGF mediated signal transduction
| Project/Area Number |
17390229
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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 | Osaka University |
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Principal Investigator |
TAKASHIMA Seiji Osaka University, Health Care Center, Assistant, 保健センター, 助手 (90379272)
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| Co-Investigator(Kenkyū-buntansha) |
KITAKAZE Masafumi National Cardiovascular Center, Department of Clinical Research and Development, Director, 臨床研究開発部, 部長 (20294069)
HORI Masatsugu Osaka University, Department of Cardiovascular Medicine, Professor, 医学系研究科, 教授 (20124779)
MINAMINO Tetsuo Osaka University, Department of Cardiovascular Medicine, Assistant, 医学系研究科, 助手 (30379234)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥15,400,000 (Direct Cost: ¥15,400,000)
Fiscal Year 2006: ¥6,300,000 (Direct Cost: ¥6,300,000)
Fiscal Year 2005: ¥9,100,000 (Direct Cost: ¥9,100,000)
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| Keywords | Heart Failure / Growth Factor / drug discovery / contraction-excitation coupling / cardiotonic drug / zebrafish |
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| Research Abstract |
Dilated Cardiomyopathy is most important disease in cardiovascular field. In this research project, we focused on the identification of new therapeutic targets of heart failure. We established mice lacking growth factor HB-EGF. These mice suffered heart failure spontaneously and the pathological and physiological phenotypes are quite similar to these of human dilated cardiomyopahty. Using this animal model and human cases of cardiomyopaty, we examined the expression profile and screened out candidate genes which involved in the pathophysiology of heart failure. Among them we focused on the novel cardiac specific myosin light chain kinase named cardiac-MLCK This novel kinase was specifically expressed in heart and phsphorirates cardiac specific myosin light chain both in vivo and in vitro. Knock down of cardiac-MLCK in zebrafish caused sever impairment of cardiac development, suggesting its important role of cardiac development. Also in rat cultured cardiomyocytes, reducing expression of cardiac-MLCK caused impairment of cardiac sarcomere assembly. These data suggests that cardiac-MLCK is indispensable kinase of cardiac myosin light chain and essential for sarcomere assembly. Since MLCK expression was severely downregulated in cardiomyocyte in heart failure, reduced cardiac-MLCK may cause the insufficient sarcomere assembly resulting heart dysfunction. In fact the mutation of cardiac myosin light chain which is substrate of cardiac-MLCK is known to cause cardiomyopathy, indicating this substrate-kinase reaction is important for sarcomere assembly and its impairment causes cardiomyopathy. In conclusion we could successfully cloned out new therapeutic target of heart failure, cardiac-MLCK, using expression profiling of heart failure samples of model animal and human. Cardiac MLCK is potential target for cardiomyopathy. We are now screening other therapeutic targets using the same data base.
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Report
(3 results)
Research Products
(13 results)
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[Journal Article] A Novel Cardiac Myosin Light Chain Kinase Regulates Sarcomere Assembly in the Vertebrate Heart.2007
Author(s)
Osamu Seguchi, Seiji Takashima, Satoru Yamazaki, Masanori Asakura, Yoshihiro Asano, Yasunori Shintani, Masakatsu Wakeno, Tetsuo Minamino, Hiroya Kondo, Hidehiko Furukawa, Kenji Nakamaru, Asuka NaitoTomoko Takahashi, Toshiaki Ohtsuka, Koichi Kawakami, Tadashi Isomura, Soichiro Kitamura, Hitonobu Tomoike, Naoki Mochizuki, Masafumi Kitakaze
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Journal Title
J. of Clin.Invest. (in press)
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling.2006
Author(s)
Shintani, Y., Takashima, S., Asano, Y., Kato, H., Liao, Y., Yamazaki, S., Tsukamoto, 0., Seguchi, O., Yamamoto, H., Fukushima, T., Sugahara, K., Kitakaze, M., Hori, M.
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Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Long-term stimulation of adenosine A2b receptors begun after myocardial infarction prevents cardiac remodeling in rats.2006
Author(s)
Wakeno, M., Minamino, T., Seguchi, O., Okazaki, H., Tsukamoto, O., Okada, K., Hirata, A., Fujita, M., Asanuma, H., Kim, J., Komamura, K., Takashima, S., Mochizuki, N., Kitakaze, M.
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Journal Title
Circulation. 114
Pages: 1923-32
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The antagonism of aldosterone receptor prevents the development of hypertensive heart failure induced by chronic inhibition of nitric oxide synthesis in rats.2006
Author(s)
Tsukamoto, O., Minamino, T., Sanada, S., Okada, K., Hirata, A., Fujita, M., Shintani, Y., Yulin, L., Asano, Y, Takashima, S., Yamasaki, S., Tomoike, H., Hori, M., Kitakaze, M.
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Journal Title
Cardiovasc Drugs Ther 20
Pages: 93-102
Description
「研究成果報告書概要(欧文)」より
Related Report
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