| Co-Investigator(Kenkyū-buntansha) |
SUGITA Naohisa Tanabe Pharmaceutical Co., Drug Discovery Research Center, Chief Researcher, 創薬研究所, 主任研究員
TASHIRO Seiki The University of Tokushima, School of Medicine, Professor, 医学部, 教授 (30040249)
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| Budget Amount *help |
¥5,100,000 (Direct Cost: ¥5,100,000)
Fiscal Year 2002: ¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 2001: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Research Abstract |
In response to various environmental stresses, mammalian cells induce a set of proteins called heat shock proteins (HSP). Overproduction of HSP, particularly a stress-inducible 70-kDa protein (Hsp70), results in the acquisition of tolerance against various types of stresses. Over the last 10 years, various experiments have been performed to examine clinical applications of Hsp70, using heat-shocked animals and gene targeting animals. At the same time, several groups introduced chaperone inducers that safely and selectively induce Hsp70. An acyclic isoprenoid, geranylgeranylacetone (GGA), was introduced for the first time as a non-toxic Hsp70 inducer, which selectively and safely induced Hsp70 in cultured guinea pig gastric mucosal cells and rat gastric mucosa, and suppressed ethanol-induced cell damage and stress ulcer formation, respectively. GGA can also prime other types of cells for enhanced induction of Hsp70, when exposed to subsequent stress. Pretreatment of rats with this compo
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und markedly rendered ischemia-reperfusion injury of the rat liver, small intestine, or heart, and improved survival after 95% hepatectomy as well as liver transplantation. In this study, we screened 12 derivatives of acyclic polyisoprenoid using primary cultured guinea pig gastric mucosal cells and rat hepotocytes and found that geranylgeraniol (GGO) was the most effective inducer for Hsp70 and exerted the most potent cytoprotective actions on these cells. The Hsp70-inducing action of GGO was confirmed by ischemia-reperfusion injury of rat livers. However, we failed to detect any beneficial effects on a rat liver transplantation model. GGA can block insult-induced apoptotic pathways at multiple steps ; it inhibited activation of c-Jun N-terminal kinases, decline of mitochondrial membrane potential, and formation of apoptosome by binding with Apafl. Recently, GGA has been shown to induce thioredoxin and anti-viral genes, suggesting that GGA may exhibit cytoprotective actions independently of Hsp70 induction. In addition to the Hsp70 inducer, such as GGA or GGO, new compounds targeting ER chaperones may be useful for the treatment of folding diseases. Less
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