| Project/Area Number |
14370220
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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 | The University of Tokyo |
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Principal Investigator |
MAEMURA Koji The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (90282649)
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| Co-Investigator(Kenkyū-buntansha) |
HAYASHI Dobun The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (80313104)
NAGAI Ryozo The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (60207975)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2003: ¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2002: ¥7,200,000 (Direct Cost: ¥7,200,000)
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| Keywords | circadian rhythm / biological clock / cardiovascular function / molecular biology / transgenic mouse / myocardial infraction / endothelial cell / microarray |
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| Research Abstract |
Human physiological activities are under the control of circadian rhythm, and the internal biological clock is responsible for this rhythmicity. Although increasing evidence has shown the existence of biological clocks in peripheral tissues, the functional relevance of.the peripheral clock still remains to be elucidated. Cardiovascular function and frequencies of onset of cardiovascular diseases show circadian oscillation. Furthermore, cultured vascular endothelial cells and cardiomyocytes showed circadian oscillation of clock genes expression, suggesting the existence of the peripheral clock in cardiovascular systems. To elucidate the functional relevance of the peripheral clock in cardiovascular system, we tried to identify the target genes of the peripheral clock. One of the candidate genes we identified was PAT-1. We demonstrated that PAI-1 mRNA levels exhibited circadian variation in mouse peripheral organs. Then, we demonstrated that CLOCK and BMAL increased PAI-1 gene expression
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mediated through the E-box sites. The circadian oscillation of PAI-1 gene expression is responsible for the decreased fibrinolytic activity that attributes to the morning onset of myocardial infarction. To further identify the target genes of the peripheral clock in cardiovascular systems, we performed cDNA microarray analysis using RNA from vascular endothelial cells treated with adenoviruses expressing CLOCK and CLIF/BMAL2. One of the genes identified by this method was DEC1, a bHLH transcription factor that was recently reported as a component of the biological clock. Now, we are analyzing other genes we isolated as candidate genes regulated by the peripheral clock. Taken together, these results suggest that cardiovascular systems have their own peripheral, clocks and at least in part, they may regulate the circadian oscillation of cardiovascular function directly. We further generated transgenic mice whose biological clocks are destroyed specifically in vascular endothelial cells. Using these mice, we are about to analyze the role of peripheral clock separately from the central clock. These results potentially provide a molecular basis for the circadian variation of cardiovascular function and novel strategies for the treatment of cardiovascular diseases. Less
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