The long-term objective of this proposal is to train the principal investigator to become an independent physician-scientist. The principal investigator has completed fellowship training in pediatric hematology/oncology at Washington University and will now build on her initial laboratory experience through a structured program of didactic learning and scientific mentoring. Robert Strieter, a world-class authority on cytokines and lung biology; Enrique Rozengurt, a cell signaling expert; and Brian Hackett, an expert in the field of lung developmental biology, will mentor the scientific development of the principal investigator. In addition, an advisory committee of developmental biologists and pulmonologists will assist in providing research and career guidance. The Department of Pediatrics at UCLA, with its long track record of training physician-scientists, will provide an excellent, nurturing environment. The research proposal aims to identify the mechanisms regulating the loss of cilia and the breakdown of the apical cytoskeleton in certain pulmonary diseases. Various respiratory diseases such as asthma and RSV infection, which are characterized by increases in the cytokines IL-13 and IL-4, demonstrate loss of cilia with basal body mislocalization. The transcription factor, Foxj1, is essential for axoneme stability through its maintenance of basal body anchoring to the apical cytoskeleton. An absence of foxj1 results in an absence of cilia with mislocalization of basal bodies.
The specific aims i n this proposal are designed to elucidate the role of IL-13 and IL-4 in the regulation of foxj1 expression, as well as their role in regulating the apical cytoskeleton and cilia stability. The regulation of the foxj1 promoter by IL-13 and IL-4 through their signal transduction pathways and activation of STAT-6 will be examined by transfection of a lung cell line. Cultured, differentiated human airway epithelial cells will be treated with IL-13 and IL-4 to examine the effect on foxj1, cilia and the apical cytoskeleton. RSV infection in wild type and STAT-6-/- mice will be used as a model to examine regulation of foxj1, the apical cytoskeleton and the signal transduction pathways involved in abnormal mucociliary clearance in response to RSV infection.
