| Project/Area Number |
14104012
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| Research Category |
Grant-in-Aid for Scientific Research (S)
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| Allocation Type | Single-year Grants |
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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 |
NAGAI Ryozo The University of Tokyo, Faculty of Medicine, Professor, 医学部附属病院, 教授 (60207975)
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| Co-Investigator(Kenkyū-buntansha) |
MAEMURA Koji The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (90282649)
MANABE Ichiro The University of Tokyo, Graduate School of Medicine, Lecturer, 大学院医学系研究科, 科学技術振興特任教員 (70359628)
廣井 透雄 東京大学, 医学部附属病院, 助手 (30311624)
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| Project Period (FY) |
2002 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥107,640,000 (Direct Cost: ¥82,800,000、Indirect Cost: ¥24,840,000)
Fiscal Year 2006: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2005: ¥22,360,000 (Direct Cost: ¥17,200,000、Indirect Cost: ¥5,160,000)
Fiscal Year 2004: ¥22,360,000 (Direct Cost: ¥17,200,000、Indirect Cost: ¥5,160,000)
Fiscal Year 2003: ¥22,360,000 (Direct Cost: ¥17,200,000、Indirect Cost: ¥5,160,000)
Fiscal Year 2002: ¥23,790,000 (Direct Cost: ¥18,300,000、Indirect Cost: ¥5,490,000)
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| Keywords | tissue remodeling / transcription factor / drug discovery / atherosclerosis / metabolic syndrome / gene engineered mouse / klotho / KLF5 / Klf5 / 心肥大 / 老化 / 線維化 |
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| Research Abstract |
External stress activates local cells of the mesenchymal origin (e.g., fibroblasts and smooth muscle cells) and inflammatory cells. Interactions between these cells promote fibrosis, organ hypertrophy, and structural remodeling. These changes affect the function of organs and result in organ failure including heart failure, renal failure, and liver failure. Thus, elucidation of molecular mechanisms underlying the tissue remodeling would lead to development novel therapeutic strategies for protection of normal organ function. We identified a Kruppel-like zinc finger transcription factor BTEB2 that is important for atherosclerosis, restenosis after angioplasty, tissue fibrosis, and cardiac hypertrophy. We also found that the ageing related factor Klotho inhibits tissue remodeling of the cardiovascular system. In this research project, we have analyzed transcriptional regulation and signal transduction that control tissue remodeling. The goals of the project were : 1)elucidation of the transcription factor network involved in activation of mesenchymal cells in tissue remodeling ; 2)elucidation of signal transduction mechanisms involved in the protective function of the Klotho factor against stress in the cardiovascular system ; and 3)development of drugs targeting transcription factors and humoral factors that are important for remodeling. We demonstrated that KLF5 plays essential roles in stress responses in both cardiovascular and metabolic systems. KLF5 interacts with transcription factors, such as PPARγ and RARα, cofactors, such as p300, and apoptosis-related genes, such as PARP to control stress response and to mediate tissue remodeling. To develop novel therapeutics targeting the KLF5 molecular network, we found a synthetic retinoid Am80 disrupts the interaction between KLF5 and RARα and inhibits KLF5's function. We showed that Am80 inhibited neointima formation and atherogenesis. We also demonstrate that klotho exhibits vascular protective effects.
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