| Project/Area Number |
15390243
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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 | Akita University |
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Principal Investigator |
ITO Hiroshi Akita University, School of Medicine, Professor, 医学部, 教授 (10232464)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥14,100,000 (Direct Cost: ¥14,100,000)
Fiscal Year 2005: ¥4,700,000 (Direct Cost: ¥4,700,000)
Fiscal Year 2004: ¥4,500,000 (Direct Cost: ¥4,500,000)
Fiscal Year 2003: ¥4,900,000 (Direct Cost: ¥4,900,000)
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| Keywords | cardiac myocytes / cell cycle / cyclin D1 / NLS / regeneration therapy / cyclin D1 / アデノウィルスベクター |
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| Research Abstract |
Myocyte loss caused by cardiovascular diseases leads to irreversible deficits in cardiac function, because of the inability of the remaining myocytes to reconstitute the damaged myocardium. To elucidate the inhibitory mechanism of cardiomyocyte proliferation would have therapeutic importance for myocardium regeneration. We show that cyclin D1, a key regulator for the G1-to-S phase transition, is induced by mitogenic stimulation but localizes predominantly cytoplasmic in neonatal cardiomyocytes. Nevertheless, cytoplasmic cyclin D1 assembled with cyclin-dependent kinase 4 (CDK4), and p21^<Cip1>, which provides nuclear localization signals (NLSs) for the cyclin D1/CDK4 complex. Coexpression of CDK4 with a cyclin D1 mutant directly linked to viral NLSs, but not wild-type cyclin D1, induced cell cycle progression leading to cell division. Moreover, cyclin D1/CDK4 nuclear import promoted cell cycle reentry of cardiomyocytes in the adult rat heart. Further we performed in vivo study using rats with heart failure by introducing the adenovirus vector in the heart. Cyclin D1 nuclear import is critical for inducing proliferation of cardiomyocytes that otherwise have quit limited proliferative capacity, and this can be applied to a novel therapeutic strategy for heart failure.
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