| Project/Area Number |
14570625
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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 |
Neurology
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| Research Institution | Nippon Medical School |
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Principal Investigator |
ASOH Sadamitsu Nippon Medical School, Institute of Development and Aging Sciences, Associate Professor, 老人病研究所, 助教授 (70167914)
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| Co-Investigator(Kenkyū-buntansha) |
OHTA Shigeo Nippon Medical School, Institute of Development and Aging Sciences, Professor, 老人病研究所, 教授 (00125832)
KATSURA Ken-ichiro Nippon Medical School, Second Department of Internal Medicine, Lecturer, 医学部, 講師 (50297892)
OHSAWA Ikuroh Nippon Medical School, Institute of Development and Aging Sciences, Lecturer, 老人病研究所, 講師 (30343586)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2004: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2003: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2002: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | Brain ischemia / Apoptosis / Bcl-xL / Glutamate toxicity / Calcium / Protein transduction domain / Necrosis / Freezing and thawing / protein transduction domain / 中大脳動脈 / 遅発性神経細胞死 / 海馬 / グルタミン酸毒素 |
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| Research Abstract |
Preventing massive cell death is an important therapeutic strategy for various injuries and disorders. Few practical therapies have been explored for clinical applications to ischemic cerebral infarction. Protein therapeutics has the advantage of delivering proteins in a short period of time. We have engineered the anti-apoptotic bcl-x gene to generate the super anti-apoptotic factor, FNK, with a more powerful cytoprotective activity. In this project, we fused the protein transduction domain(PTD) of the HIV/Tat protein to FNK, and used the construct in an animal model of ischemic brain injury. When added into culture media of human neuroblastoma cells and rat neocortical neurons, PTD-FNK rapidly transduced into cells to protect the neuroblastomas and neurons from staurosporine-induced apoptosis and glutamate-induced excitotoxicity, respectively. PTD-FNK affected the cytosolic movement of calcium ions, which may relate to its neuroprotective action. When injected intraperitoneally into
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gerbils, PTD-FNK prevented delayed neuronal death in the hippocampus caused by transient global ischemia. When a focal ischemic model rat was intravenously post-treated with the PTD-FNK protein, ischemic injury was improved in terms of infarction volume (total and cortical) and neurological symptoms. Interestingly, combined injection of PTD-FNK and an immunosuppressant FK506 showed the stronger protective effect to reduce the infarction volume, exhibit a continuous effect for 1 week after the treatment and extend the therapeutic window by 3 hr. These results suggest that PTD-FNK has a potential for clinical utility as a novel protein therapeutic strategy to prevent cell death in the brain. During performing the project, we, in addition, revealed that PTD-FNK penetrates the dense matrix of cartilage to reach chondrocytes in slice culture of cartilage and protect the chondrocytes from death induced by death stimuli, prevents necrosis and hepatic injury with zonal death induced by carbon tetrachloride, and protect cells from death induced by freezing and thawing. Less
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