| Budget Amount *help |
¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
Mammalian cardiomyocytes are terminally differentiated and do not proliferated in adults. Recently we have reported that expression of cyclin D1 tagged with a nuclear localization signal (D1NLS) and Skp2, which is ubiquitin E3 ligase for p27, allows cardiomyocytes to re-enter cell cycle. It has remained unknown, however, if such cardiomyocytes undergo normal cell division. In this study, we show that cardiomyocytes in culture expressing D1NLS/CDK4 and Skp2 upregulate G1, S, and G2M cyclins, regulators of DNA replication (Orc6 and Geminin), and also CDK inhibitors (INK4 and CIP.KIP family). In a rat myocardial infarction model, D1NLS, CDK4, Skp2 induce an indicator of S phase (Ki67), M phase (phosphorylated histone H3), and cytokinesis (Aurora B/Survivin). These data demonstrate that mammalian cardiomyocytes can be induced to undergo complete cell division in vivo through acceleration (D1NLS/CDK4) and release from breakes (Skp2) of cell cycle. These findings have clinical implications since expression of D1NLS/CDK4 and Skp2 reduces the size of infarction and improves parameters of left ventricular function and lung homeostasis. Thus, in situ proliferation of adult cardiomyocytes may provide a novel therapeutic approach for prevention and treatment of heart failure.
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