| Co-Investigator(Kenkyū-buntansha) |
HIRANO Makito Nara Medical University, Dept.Neurology, Assistant Professor, 医学部, 講師 (50347548)
MURATA Ken-ya Nara Medical University, Dept.Neurology, Assistant Professor, 医学部, 講師 (90264853)
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| Budget Amount *help |
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2003: ¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 2002: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Humanin (FIN) is a 24-amino-acid peptide that protects cells from apoptosis induced by mutant Alzheimer's disease (AD) genes, but its protective effect against other cytotoxic factors remains unclear. The aim of this project is to establish the therapeutic potential of HN for various diseases or types of cell death other than AD. The effect on non-specific neuronal cell death was tested using rat pheochromocytoma PC12 cells undergoing apoptosis after serum deprivation. HN significantly decreased cell death and fragmentation of nuclear DNA with the suppression of caspase 3 activity. To further extend the applicability of FIN, we examined human lymphocytes cultured under serum-deprived condition. FIN increased ATP level and suppressed cell death, suggesting that this peptide may be used for the treatment of disorders with ATP deficiency, such as Parkinsons disease and mitochondrial diseases (MDs). Therefore, we tested FIN in mitochondrial encephalopathy, lactic acidosis, and stroke-like
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episodes (MELAS), one of the most common MDs. Readily obtainable peripheral lymphocytes from patients with MELAS were cultured under serum-deprived condition, which significantly decreased the ATP levels in MELAS cells compared with those in controls. FIN increased the ATP levels, and suppressed cell death and mitochondrial DNA copy number. Similar cytoprotective and ATP-producing effects were observed in human neuroblastoma SK-N-MC cells and rhabdomyosarcoma TE671 cells, suggesting that FIN may alleviate the impairment in brain and muscle, which are the tissues predominantly involved in MELAS because of high ATP demand. Apoptosis may be a defense mechanism to remove cells with increased abnormal mitochondria in response to ATP deficiency and formation of reactive oxygen species, however, it may disturb cellular function, leading to further tissue damages in MELAS. HN breaks this vicious circle, and therefore, it is a promising therapeutic candidate for MDs. In conclusion, we have provided experimental evidence for the broader therapeutic spectrum of HN. Less
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