| Project/Area Number |
15390384
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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 |
General surgery
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| Research Institution | Keio University |
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Principal Investigator |
SHIMAZU Motohide Keio University, Department of Medicine, Associate Professor, 医学部, 専任講師 (70124948)
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| Co-Investigator(Kenkyū-buntansha) |
GODA Nobuhito Keio University, Department of Medicine, Associate Professor, 医学部, 専任講師 (00245549)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥5,800,000 (Direct Cost: ¥5,800,000)
Fiscal Year 2004: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2003: ¥3,000,000 (Direct Cost: ¥3,000,000)
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| Keywords | hypoxia / knockout mice / ischemia / liver regeneration / cyclin / cell cycle / hypoxia inducible factor-1 / ノックアウトマウス / 部分肝切除術 |
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| Research Abstract |
Mammalian cells have evolved to utilize molecular oxygen for energy production. Cells can respond differentially to wide ranges of oxygen concentrations through activation of varied transcriptional factors. Among them, hypoxia inducible transcription factor HIF-1 is a major regulator of hypoxic responses. This study aimed to elucidate the molecular mechanisms by which hepatic parenchymal cells adapt to hypoxic stress. To this end, we generated mice harboring a floxed HIF-1α allele, and employed the albumin-Cre transgenic line to inactivate HIF-1α gene specifically in hepatocytes. This allowed mice to escape from embryonic lethality and delete HIF-1α gene exclusively in hepatocytes. Histochemical analyses showed that distances between terminal central venule and its closest portal vessel in HIF-1α deficient livers were longer than those in wild type by 50μm. However, expressions of glycolytic enzymes, most of which are known to be regulated by HIF-1 under hypoxia and predominantly present in the pericentral regions of liver, were not disturbed by inactivation of HIF-1α gene. We next subjected mice to 70% partial hepatectomy (PH) to introduce molecular signals to regenerate. Animals were sacrificed at intervals after the surgery, and the remnant liver was harvested and analyzed. We found that regenerating processes in the mutant mice were retarded during the early post-operative periods compared to those observed in the control mice. Moreover, cyclin-dependent kinases and several cell cycle regulators were affected, resulting in inefficient G1-S phase progression. The present study suggests that HIF-1 serves as a putative regulator for liver regeneration.
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