Regulation of Respiratory Epithelial Cell Homeostasis

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DESCRIPTION (provided by applicant): Acute and chronic airway injury and inflammation cause airway remodeling and airspace abnormalities that contribute to the pathogenesis of pulmonary disease in children and adults. Cellular and molecular processes mediating airway remodeling, fibrosis and emphysema remain poorly understood, but contribute to the pathogenesis of common lung disorders, including COPD, CF, asthma, BPD, pulmonary fibrosis, and emphysema. The hypothesis underlying the current program project grant is that disruption of respiratory epithelial cell homeostasis leads to altered airway function and alveolar homeostasis which, in turn, contributes to airway remodeling and emphysema common to many chronic lung diseases. Four projects are proposed to identify and characterize target/modifier genes and transcriptional programs that regulate homeostatic mechanisms (differentiation and cytoprotective responses) of respiratory epithelial cells. Project 1 will explore the role of ERAD (ER associated degradation) associated transcription in protecting the respiratory epithelium against intrinsic lung injury arising from SP-C mutations that cause protein misfolding. Project 2 will identify genes that modulate the severity of interstitial lung disease associated with deficiency of SP-C in type II epithelial cells. Project 3 will assess the ability of STAT-3 to protect the epithelium against extrinsic lung injury caused by hyperoxia. Project 4 will examine the role of the epithelial cell transcription factors Foxa1 and Foxa2 in regulating epithelial cell differentiation and alveolarization in the postnatal lung. These four projects will be supported by two cores that facilitate target gene identification (Microarray/Bioinformatics Core) and morphologic analyses of transgenic and gene targeted mice (Morphology Core). It is anticipated that this PPG will lead to identification of new transcriptional programs and signal pathways that may significantly impact our understanding of lung disease and new therapeutic targets for the treatment of these diseases.