RSV Uses Double-Stranded RNA Receptors to Inhibit p53 and Prolong Cell Survival

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DESCRIPTION (provided by applicant): This application is to support the development of Dr. Dayna Groskreutz into an independent investigator and an accomplished physician-scientist. Dr. Gary Hunninghake will assume the responsibility as mentor to ensure the success of the career development plan. Dr. Groskreutz has already taken courses in general research principles and graduate immunology, and career development during this K-08 award will include further coursework in immunology, virology, cell and molecular biology, study design, and statistical methods. The proposed research investigates the effect of RSV infection on double-stranded RNA (dsRNA) receptors in airway epithelial cells and examines how these dsRNA receptors modulate p53 to delay apoptosis and allow for enhanced viral replication. In Aim 1, Dr. Groskreutz will investigate the effect of RSV on the expression and location of dsRNA receptors. In addition, their effect on p53 will be determined by blocking the expression of the dsRNA receptors and evaluating for a change in p53 protein. In Aim 2, Dr. Groskreutz will examine the biological effect of RSV-induced changes in p53 protein. To this end, p53 will be over-expressed and the biological effect of preserved p53 on cell viability, RSV replication, and inflammatory pathways will be determined. Finally, Dr. Groskreutz will evaluate whether specific RSV genes play a role in modulating dsRNA receptors and p53 protein. She will develop and add RSV strains void of the expression of single genes to airway epithelial cells and evaluate their effect on dsRNA receptors and p53. Throughout Dr. Grosrkeutz's career development, she will consult with experts in immunology, virology, cell biology, pharmacology, pediatrics, and pulmonary medicine. This environment will facilitate her development into an independent investigator, and her colleagues will serve as important resources as well as provide critical review of her work. Both her mentor and her institution are committed to her success and career development. As a sign of this commitment, she joined the faculty of the Division of Pulmonary and Critical Care Medicine in July 2006. Dr. Groskreutz's research proposal has great clinical significance. RSV continues to be a perplexing and challenging clinical problem in young children, in patients with chronic lung disease, and in immunosuppressed patients. This research could provide insight into to the cell signaling pathways important to the pathogenesis of RSV infection and identify key therapeutic targets for future clinical trials. (End of Abstract)