COBRE: W & I HOSP OF RI: FAS-MEDIATED APOPTOSIS IN PERINATAL LUNG REMODELING

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Adaptation to postnatal life requires coordinated architectural and cellular remodeling of the developing lung. We have previously shown that critical time points in perinatal lung development are characterized by high levels of alveolar type II cell apoptosis. We have further determined that: 1) these episodes of increased type II cell apoptosis coincide precisely with marked upregulation of the cell death regulator Fas ligand (FasL) and its receptor Fas (APO-1, CD-95); 2) both Fas and FasL are immunolocalized to alveolar type II cells; and 3) fetal and postnatal type II cells are responsive to direct Fas-activation. These results support our central hypothesis: Fas/FasL-mediated apoptosis of alveolar type Ii cells is an important and developmentally regulated event in perinatal lung remodeling. Based on this hypothesis, we have formulated the following specific aims. In Aims 1 and 2, we will determine the effects of h yperoxia and mechanical distension/stretch on Fas/FasL signaling and apoptosis of perinatal murine type II cells in vitro and in vivo. In Aim 3, we will study the effect of type II cell-targeted tetracycline-requlated FasL overexpression in mice on perinatal type II cell apoptosis, lung remodeling, and expression of alternative apoptotic signaling pathways. We anticipate that elucidation of the molecular mechanisms regulating perinatal type II cell apoptosis will result in important insights into the developmental biology of the lung, and will lead to the identification of novel targets for therapy or prevention of diseases associated with dysregulated perinatal lung remodeling, such as bronchopulmonary dysplasia (chronic lung disease) of the newborn.