The candidate for this Mentored Clinical Scientist Development Award is committed to further career development in pulmonary research with the goal of becoming an independent investigator. Candidate qualifications for the award include an excellent academic record, two fellowship years of NIH-sponsored research with outstanding progress, and success with competitive grant applications. He is currently funded through the Parker B. Francis Foundation on a mentored career development award. The sponsor and cosponsor are established investigators in the proposed field of study, and the excellent research environment at the University of Iowa will provide didactic and practical research input at a high level. At completion of this project, the candidate will have gained expertise in epithelial cell biology, protein biochemistry, viral and human gene manipulation, RNA interference, and recombinant DMA technology. This research plan is structured to provide the candidate with a strong foundation in the cell and molecular biology of respiratory viral infection and immune defense responses in the pulmonary airway. The research plan focuses on the common respiratory pathogen respiratory syncytial virus (RSV), which has the capacity to inhibit type I interferon-dependent antiviral gene expression and airway immunity. Preliminary studies performed by the candidate demonstrate that RSV modulates type I interferon signal transduction though inhibition of the expression of Stat2 transcription factor. The central hypothesis of this proposal is that RSV induces proteasome-dependent degradation of Stat2, and this effect is mediated by specific viral nonstructural proteins. The overall goal of this proposal is to investigate the biochemical basis for RSV effects on antiviral gene expression. The novel contributions of this work will include a better understanding of interferon-mediated immune responses and RSV mechanisms to circumvent systems for host defense. Accordingly, our specific aims are to: AIM I. Determine RSV mechanisms that decrease Stat2 expression in airway epithelial cells. This aim will be accomplished by assessing the cell specificity and mechanisms that regulate Stat2 mRNA and protein expression in human airway epithelial cells after RSV infection. AIM II. Identify RSV protein(s) that inhibit type I interferon signaling in airway epithelial cells. Silencing viral gene expression by small interfering RNA's (siRNA) and use of mutant viruses, and plasmid- and viral vector- based expression of viral proteins will be used to identify RSV viral genes necessary and sufficient for inhibition of type I interferon signaling.