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

描述（由申请人提供）： 本申请旨在支持Dayna Groskreutz博士发展成为一名独立的研究人员和一名有成就的医生科学家。加里亨宁哈克博士将承担导师的责任，以确保职业发展计划的成功。Groskreutz博士已经参加了一般研究原理和研究生免疫学课程，在此K-08奖期间的职业发展将包括免疫学，病毒学，细胞和分子生物学，研究设计和统计方法的进一步课程。这项研究调查了RSV感染对气道上皮细胞中双链RNA（dsRNA）受体的影响，并研究了这些dsRNA受体如何调节p53以延迟细胞凋亡并增强病毒复制。在目标1中，Groskreutz博士将研究RSV对dsRNA受体表达和定位的影响。此外，通过阻断dsRNA受体的表达并评估p53蛋白的变化来确定它们对p53的影响。在目标2中，Groskreutz博士将研究RSV诱导的p53蛋白变化的生物学效应。为此，p53将被过表达，并且将确定保存的p53对细胞活力、RSV复制和炎症途径的生物学效应。最后，Groskreutz博士将评估特定的RSV基因是否在调节dsRNA受体和p53蛋白中发挥作用。她将开发和添加RSV菌株空的单一基因表达的气道上皮细胞，并评估其对dsRNA受体和p53的影响。在Grosrkeutz博士的职业发展过程中，她将咨询免疫学、病毒学、细胞生物学、药理学、儿科和肺部医学方面的专家。这种环境将有助于她发展成为一名独立的调查员，她的同事将作为重要的资源，并对她的工作进行严格的审查。她的导师和她的机构都致力于她的成功和职业发展。作为这一承诺的标志，她于2006年7月加入了肺和重症监护医学部。Groskreutz博士的研究建议具有重大的临床意义。RSV在幼儿、慢性肺病患者和免疫抑制患者中仍然是一个令人困惑和具有挑战性的临床问题。这项研究可以深入了解RSV感染发病机制的重要细胞信号通路，并为未来的临床试验确定关键的治疗靶点。 (End摘要）

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)