2007 Fiscal Year Final Research Report Summary
Inhibition of liver degeneration by protein transduction method using the super anti-cell death protein
| Project/Area Number |
17590687
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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 |
Gastroenterology
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| Research Institution | Nippon Medical School |
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Principal Investigator |
AOSH Sadamitsu Nippon Medical School, Institute of Gerontology, Associate Professor (70167914)
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| Co-Investigator(Kenkyū-buntansha) |
OHSAWA Ikuroh Nippon Medical School, Lecturer (30343586)
MORI Takashi Saitama Medical School, School of Medicine, Associate Professor (60239605)
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| Project Period (FY) |
2005 – 2007
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| Keywords | Drug-induced liver injury / Ischemia / renerfusion / Protein therapy / Apoptosis / Aminoglycoside / Transplantation / Acute lung injury / Amyotrophic lateral sclerosis |
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| Research Abstract |
The aim of this project is to ameliorate liver injury induced by drug or ischemia/reperfusion using the super anti-cell death protein FNK, which was generated from an anti-apoptotic protein Bcl-xL by substitution of three amino acid residues for another one within the same group, respectively. To introduce FNK protein in cells, FNK was genetically fused with the Protein Transduction Domain (PTD) of the HIV/Tat protein. The resultant fusion protein is named PTD-FNK. PTD-FNK was delivered into neuronal cells in the brain across the blood brain barrier, when intraperitoneally injected, to inhibit delayed neuronal cell death in hippocampus induced by global ischemia (Asoh, S., et. al., Proc. Natl. Acad. Sci. USA. 2002).
In this project, we have shown that systemic injection of PTD-FNK inhibits zonal necrosis of the liver induced by carbon tetrachloride, liver degeneration caused by ethanol and dexamethasone, and an early stage of liver injury (apoptosis) induced by ischemia/reperfusion. PTD-FNK suppressed an elevation of serum ALT and AST levels induced by carbon tetrachloride. It was shown that PTD-FNK maintains mitochondrial membrane potential and confer upon HepG2 cells resistance against carbon tetrachloride and TNFα. These results encouraged us to apply PTD-FNK for other experimental disease models. PTD-FNK successfully reduced brain and heart injuries caused by ischemia/reperfusion. Furthermore, PTD-FNK was delivered into inner ear cross the blood-inner ear barrier to ameliorate aminoglycoside-induced hearing loss. It was also shown that PTD-FNK enhances transplantation efficiency of bone marrow mononucleocytes and ameliorates neuronal damage in amyotrophic lateral sclerosis model, acute lung injury caused by lipopolysaccharide, and alopecia caused by anti-cancer drugs. The studies on protein therapy using PTD-FNK have been published in many international journals.
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[Presentation] 内耳とアポトーシス2005
Author(s)
渡邊 健一
Organizer
第15回日本耳科学会総会, ランチョンセミナー
Place of Presentation
大阪
Year and Date
20051000
Description
「研究成果報告書概要(和文)」より
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