| Project/Area Number |
18590793
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | Kurume University |
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Principal Investigator |
YASUKAWA Hideo Kurume University, Cardiovascular Research Institute, Assistant Professor (60289361)
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| Co-Investigator(Kenkyū-buntansha) |
SUGI Yusuke Kurume University, School of Medicine, Research Associate (40389250)
MORI Takahiro Kurume University, School of Medicine, Research Associate (80389254)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000)
Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | heart failure / cytokine / SOCS / signal transduction / gp130 / 細胞内シグナル / STAT / ストレス |
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| Research Abstract |
The JAK/STAT pathway is an evolutionary conserved essential signaling network involved in distinct cellular process including inflammation and apoptosis. Cytokines including interferons (IFNs) and interleukins activate JAK-STAT pathway. Suppressor of cytokine signaling 1 (SOCS1) and SOCS3 are cytokine or stress-inducible inhibitors of JAK-STAT pathway. We focused on innate defense mechanisms in the cardiac myocyte that are important determinants of susceptibility to infection in viral myocarditis. Either cardiac-specific transgenic expression of SOCS1 or SOCS3 has a marked effect on the susceptibility of the heart to coxsackievirus B3 (CVB) infection; however, SOCS3 ectopic expression does not affect IFN-receptor signaling or the IFN antiviral effect in isolated myocytes. Therefore, we showed that cardiac-specific knockout of gp130 increases susceptibility to CVB, demonstrating a role for gp130 signaling via activation of STAT3. These findings suggest that endogenous SOCS3 also has significant biological effect within the cardiac myocyte. To understand physiological role of SOCS3 in the cardiac myocyte, we generated cardiac-specific SOCS3 knockout mice. The mice were born at the expected Mendelian ratio, but developed cardiac dysfunction estimated by echocardiogram from 5 months of age and died with signs of dyspnea by 8 months of age. Postmortem analysis revealed significant pleural effusions and ascites, consistent with the presence of heart failure. Histological analysis showed that the heart has a thin ventricular wall with chamber dilatation; however, typical findings of a myopathic heart such as myocyte disarray, inflammation and fibrosis were only rarely observed. Ultrastructure analysis of the dilated heart samples showed intact myofibrils, mitochondria, intercalated discs and gap junctions, suggesting that the myocyte had non-structural abnormalities that led to functional impairment.
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