Bronchopulmonary dysplasia (BPD) is a prevalent pediatric respiratory lung disease, affecting ~25% of newborns with birth weight under 1500g. BPD patients suffer chronic respiratory deficiencies and are more at risk for respiratory viral infections and the development of asthma. BPD arises as a consequence of premature disruption of the normal course of development, often compounded by lung injury incurred as a side effect of oxygen supplementation and mechanical ventilation. A key feature of BPD pathology is enlargement of alveolar space. This is accompanied by an increase in myofibroblasts and disorganization of the elastin network. Whether these remodeling events are cause or consequence of alveolar enlargement is not known. To elucidate the etiology of BPD, we propose experiments in mouse models to determine the causal relationship of these defects. Existing data show fibroblast growth factor (FGF) signaling is reduced in BPD lungs, and reduction of FGF signaling in mice leads to BPD-like phenotypes. These findings suggest that FGF pathway mutant mice provide an entry point for the investigation of how BPD-like defects arise. Using these mutants, we will dissect the precise temporal and spatial requirements for FGF signaling in the perinatal period, and its precise role in lung maturation (Aim 1). We will tes the relationship between FGF and other factors implicated in lung maturation process (Aim 2). Finally, we will test whether heritable changes in FGF and FGF regulated pathways may underlie the known genetic predisposition to BPD. Our findings will not only advance basic knowledge of understudied aspects of lung biology, but will also provide insights at a molecular level of how deviation from the normal development program and external trauma may lead to the onset of BPD.
Our results will advance current knowledge on the genetic circuitry that drives normal lung sacculation and alveologenesis, two understudied aspects of lung maturation process. As the defects in animal models studied here closely mimic the pathology of children with bronchopulmonary dysplasia (BPD), our findings will lead to a better understanding of the cause of disease, and inform efforts to reduce lung injury, enhance lung repair, and prevent the development of BPD in premature infants.
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