| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Research Abstract |
Collectively, the results of this study provide evidence that the transcription factor IRF-2 is required by pancreatic acinar cells for both their development and/or maturation, and in protection against dsRNA-induced apoptosis. The latter implies that in the absence of IRF-2 expression, pancreatic acinar cells become susceptible to apoptosis induced by virus infections as well as by poly(I):polyc. Previous studies have shown that the anti-apoptotic effect of IRF-2 is mediated through the regulation of expression of IFN-inducible pro-apoptotic genes. However, the induction of the expression of these genes by poly(I):polyc was not significantly altered in pancreatic acinar cells lacking IRF-2, suggesting that genes other than the IFN-inducible pro-apoptotic genes examined here are involved.
Clinically, 10% of pancreatitis is diagnosed as idiopathic. Although we do not know at present how IRF-2-expression may be physiologically downregulated in the pancreas, it is interesting to speculate
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that some cases of idiopathic pancreatitis might be caused by latent viral infections in the presence of abnormally low concentrations of IRF-2. Intriguingly, human immunodeficiency virus (HIV) infection has often been associated with pancreatitis, and herpes virus 8/Kaposi sarcoma-associated herpes virus (HHV-8/KSHV), the casual factor in HIV-associated Kaposi sarcoma, encodes viral IRF (vIRF)-2 in open reading frame K9. An in vitro binding assay confirmed the association between recombinant vIRF-2 and cellular ERF-2, RelA, or p300, and vIRF-2 is proposed to have a dominant negative activity on IRF-2. Because KSHV has been suggested to infect the pancreas, we therefore hypothesize that it is possible that AIDS patients infected with this virus exhibit decreased IRF-2 expression in the pancreas and are therefore prone to apoptosis-induced pancreatitis after opportunistic virus infections. Study to examine in our murine model pancreatits the possible involvement of vIRF-2 derived from KSHV is underway. Less
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