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

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。适应出生后的生活需要协调的建筑和细胞重塑发育中的肺。我们之前已经表明，围产期肺发育的关键时间点以高水平的肺泡II型细胞凋亡为特征。我们进一步确定：1)这些II型细胞凋亡的增加恰好与细胞死亡调节剂Fas配体（FasL）及其受体Fas （APO-1, CD-95）的显著上调相吻合；2) Fas和FasL均免疫定位于肺泡II型细胞；3)胎儿和出生后II型细胞对fas -直接激活有反应。这些结果支持了我们的中心假设：Fas/ fasl介导的肺泡Ii型细胞凋亡是围产期肺重构中一个重要的发育调节事件。基于这一假设，我们制定了以下具体目标。在Aims 1和Aims 2中，我们将在体外和体内研究高氧和机械扩张/拉伸对围产期小鼠II型细胞Fas/FasL信号通路和凋亡的影响。在Aim 3中，我们将研究四环素调控的II型细胞FasL过表达对围产期II型细胞凋亡、肺重塑和其他凋亡信号通路表达的影响。我们预计，对围产期II型细胞凋亡调控的分子机制的阐明将对肺部发育生物学产生重要的见解，并将导致确定新的靶点，用于治疗或预防与围产期肺重塑失调相关的疾病，如新生儿支气管肺发育不良（慢性肺病）。

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.