The goal of this SCOR proposal is to combine basic and clinical research approaches to investigate mechanisms of injury, inflammation and repair of the developing lung that underlie the pathogenesis of chronic lung disease (CLD) of infancy. Using gene targeting approaches in animal models of CLD-like injury, the investigators aim to identify and analyze how specific effector molecules alter developmental cellular behaviors. Project 1 utilizes a mouse model of glucocorticord deficiency (corticotrophin-releasing hormone gene targeted deletion) to investigate glucocorticord-responsive molecules critical for normal alveolarization during a narrow developmental window. Project 2 investigates the role of bombesin-like peptide (BLP) in lung inflammation and disruption of alveolarization in a mouse model of hyperoxic injury and in clinical studies examines how BLP may be used to predict the incidence and severity of CLD in newborn ventilated infants. Project 3 employs lung-targeted constitutive and inducible heme oxygenase-1 (HO-1) gene expression mouse models to explore the role of this enzyme in modulating pro-inflammatory pathways that lead to CLD-like injury. Project 4 utilizes syndecan-1 and syndecan-4 null mice to study how injury-associated induction and shedding of syndecans could contribute to the inflammation, poor repair, increased susceptibility to infection and abnormal alveolar and vascular development seen in the lungs of infants with CLD. Project 5 explores mechanisms by which hypoxia, hyperoxia, and infection lead to enhanced airway hyper-responsiveness using established models of airway inflammation. Each project will have close collaboration with the animal model core (Core B) which will (i) coordinate animal breeding of the various transgenic and knockout mice to be shared by project investigators, (ii) maintain and orchestrate hyperoxic and hypoxic animal models, and (iii) coordinate and facilitate the DNA microarray to analyze lung injury and inflammation in the mouse. The Clinical and Biostatistical Core (Core A) will collaborate closely with all SCOR investigators to (i) formulate testable clinical hypotheses based on insights from lab studies, (ii) provide samples and clinical data from ventilated newborns at risk for CLD, and (iii) generate statistical analyses and study designs. Core D, Administrative Core, will orchestrate these interdisciplinary efforts, manage the distribution of funds and efforts and create a cohesive, highly collaborative SCOR research community. The long-term goal of this integrated approach is to facilitate development of new methods for the prevention and treatment of CLD.
