| Budget Amount *help |
¥5,400,000 (Direct Cost: ¥5,400,000)
Fiscal Year 1986: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1985: ¥3,700,000 (Direct Cost: ¥3,700,000)
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| Research Abstract |
2',5'-oligoadenylate (2-5A) synthetase is one of the enzymes induced by interferons (IFN) in cells and is considered to play a central role in antiviral activity, cell growth inhibition and regulation of differentiation. The enzyme catalyzes the elongation of AMP with 2'-phosphodiester linkages using ATP as a substrate in the presence of doubli-stranded RNA. The synthetized 2-5A activates a latent endonuclease and leads to preferential degradation of viral mRNA. By the way, for the defence to viral infections, the non-specific defence mechanism of IFN plays a important role in addition to the specific defence mechanism on antibody and cellular immunity. The abnormal state of failure to viral infections is immunodeficiency disease. We investigated the biochemical mechanism of susceptibility to viral infections in severe combined immunodeficiency disease (SCID) with adenosine deaminase (ADA) deficiency, which is best studied from the view point of the onset mechanism. For this, I measure
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d the 2-5A synthetase activity in human cell lines treated with deoxycoformycin (dCF), which is the specific inhibitor to ADA. For the model of ADA deficient SCID, deoxyadenosine (dAdo), the substrate of ADA, needs to be added in the culture medium. After this, I checked the activity of 2-5A synthetase. From this experiment, it became clear that the inhibitor to 2-5A synthetase was induced in proportion to the increase of dAdo concentration. This inhibitor was neither 2'-phosphodiesterase nor dATP. 2'-phosphodiesterase degrades 2-5A. dATP is a competitive inhibitor to 2-5A synthetase. The molecular weight of this inhibitor was more than 30,000 and the inhibitor was inactivated after the heat treatment of 56 C for 30 min. From this result, the inhibitor was thought to be a protein. In addition, it was speculated that hypomethylation, which is observed in ADA inhibited cells in the presence of dAdo, was associated with the induction of the inhibitor. And this seems to be one of causes for the susceptibility to viral infections in ADA deficient SCID. Less
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