We have previously identified a cellular process that modifies pre-mRNA sequences via an RNA-specific adenosine deaminase or ADAR. Recently, we showed that ADAR1 is induced in macrophages by various infectious agents, including bacteria, viruses, and pathogenic toxins. In mice suffering from endotoxin-induced inflammation, we demonstrate that 5% of the adenosines found in mRNA are converted to inosine. We further show that up to 20% of adenosines in mRNA can be converted to inosine in cells transiently expressing ADAR1. With such high levels of inosine in mRNA, the translated proteins may differ dramatically from those encoded in the genome and the repertoire of protein production could be greatly amplified. RNA processing may also be substantially affected by the presence of inosine. Indeed, we found that the phosphorylation of elF2a is suppressed and the expression of dsRNA protein kinase (PKR) and 2',5'-oligoadenylate synthetase (2'5'OAS) is downregulated in cells that overexpress ADAR1. Therefore, we hypothesize that ADAR1 functions to sustain protein synthesis during infections, and antagonize inflammatory responses at certain stages of infection. Researches to confirm this hypothesis will lead me to disease-oriented studies in transgenic animals that are currently undeveloped in my laboratory. Receipt of the K02 award will allow me to devote 90% of my effort on the proposed research, meaningfully expand my collaborations with high quality scientists, and firmly establish the new lines of investigation to develop skills in these areas and to demonstrate increasing productivity. During award period, we plan to elucidate the physiological function of ADAR1 in modulating host response to infections. The first specific aim is to characterize the role of ADAR1 in disease models of pneumonia and endotoxemia in ADAR1 transgenic mice. Homozygous transgenic mice expressing an ADAR1-EGFP chimera will be produced. Endotoxin and adenovirus-induced acute inflammation will be established and characterized in these animals. The second specific aim proposes to elucidate the mechanism of ADARl-mediated RNA degradation in response to infectious agents. The last aim is to characterize the role of ADAR1 in modulating phosphorylation cascades in the mouse models of pneumonia and endotoxemia using protein array technique. ? ?
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| Nie, Yongzhan; Hammond, Graeme L; Yang, Jing-Hua (2007) Double-stranded RNA deaminase ADAR1 increases host susceptibility to virus infection. J Virol 81:917-23 |
| Nie, Yongzhan; Ding, Li; Kao, Peter N et al. (2005) ADAR1 interacts with NF90 through double-stranded RNA and regulates NF90-mediated gene expression independently of RNA editing. Mol Cell Biol 25:6956-63 |
