| Project/Area Number |
17590687
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Research Field |
Gastroenterology
|
|---|
| Research Institution | Nippon Medical School |
|---|
Principal Investigator |
AOSH Sadamitsu Nippon Medical School, Institute of Gerontology, Associate Professor (70167914)
|
|---|
| Co-Investigator(Kenkyū-buntansha) |
OHSAWA Ikuroh Nippon Medical School, Lecturer (30343586)
MORI Takashi Saitama Medical School, School of Medicine, Associate Professor (60239605)
|
|---|
| Project Period (FY) |
2005 – 2007
|
| Project Status |
Completed (Fiscal Year 2007)
|
| Budget Amount *help |
¥3,340,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥240,000)
Fiscal Year 2007: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2006: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
|
|---|
| Keywords | Drug-induced liver injury / Ischemia / renerfusion / Protein therapy / Apoptosis / Aminoglycoside / Transplantation / Acute lung injury / Amyotrophic lateral sclerosis / 抗癌剤 / 肺傷害 / ネクローシス / Protein transduction domain / 肝臓 / bcl-x / 薬物性急性肝炎 / 四塩化炭素 / Ptortein transduction domain / Bcl-x |
|---|
| 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.
|
