| Project/Area Number |
15209027
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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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 | GIFU UNIVERSITY |
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Principal Investigator |
FUJIWARA Hisayoshi Gifu University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (80115930)
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| Co-Investigator(Kenkyū-buntansha) |
TAKEMURA Genzou Gifu University, University Hospital, Lecturer, 医学部附属病院, 講師 (40283311)
ARAI Masazumi Gifu University, University Hospital, Lecturer, 医学部附属病院, 講師 (00202721)
KOSAI Kenichirou Kurume University, Cognitive and Molecular Research Institute of Brain Diseases, Professor, 高次脳疾患研究所, 教授 (90258418)
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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 |
¥43,940,000 (Direct Cost: ¥33,800,000、Indirect Cost: ¥10,140,000)
Fiscal Year 2005: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000)
Fiscal Year 2004: ¥10,400,000 (Direct Cost: ¥8,000,000、Indirect Cost: ¥2,400,000)
Fiscal Year 2003: ¥23,140,000 (Direct Cost: ¥17,800,000、Indirect Cost: ¥5,340,000)
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| Keywords | dilated cardiomyopathy / cytokine / autophagy / G-CSF / heart failure / remodeling / apotosis / cardiomyocyte regeneration / DCMハムスターモデル / 慢性心不全 / 梗塞後慢性心不全 / G-CSF / G-CSF受容体 / MMP / TNF-α / 再生医療 / オートファジイ / HGF / 遺伝子治療 / ハムスターUM-X7.1 / 再生療法 / 顆粒球コロニー刺激因子(G-CSF) / 繊維化抑制 / 心筋細胞再生 / 心機能の改善 |
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| Research Abstract |
In UM-X7.1 strain hamsters, a model of human dilated cardiomyopathy, heart failure progressively develops and a half of them die by 30 weeks old. We ultrastructurally found typical autophagic vacuoles including degraded mitochondria, glycogen granules, and myelin-like figures and overexpressed ubiquitin, cathepsin D and Rab7 in many cardiomyocytes of this model. Importantly, most cardiomyocytes with leaky plasma membrane were positive for cathepsin D, suggesting a direct linkage between autophagic degeneration and cell death. Meanwhile, cardiomyocyte apoptosis appeared insignificant. Injection of granulocyte colony-stimulating factor (10 μg/kg/day) 5 days/week for 15 weeks, started at 15 weeks of age, improved survival among 30-week-old hamsters (100% vs. 53% in the untreated hamsters, p<0.0001), ventricular function and remodeling, increased cardiomyocyte size, and reduced myocardial fibrosis, followed by a dramatic reduction in the autophagic findings. It also resulted in downregulation of tumor necrosis factor-α and increase in activities of Akt, signal transducer and activator of transcription-3, and matrix metalloproteinases. However, there was no clear evidence of transdifferentiation from bone marrow cells into cardiomyocytes. In conclusion, autophagic death is important for cardiomyocyte loss in the cardiomyopathic hamster and granulocyte colony-stimulating factor has the beneficial effect mainly via antiautophagic mechanism rather than antiapoptosis or regeneration.
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