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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 适应出生后的生活需要协调的结构和细胞重建的发展肺。我们以前已经表明，在围产期肺发育的关键时间点的特点是高水平的肺泡II型细胞凋亡。我们进一步确定：1）这些增加的II型细胞凋亡事件与细胞死亡调节因子Fas配体（FasL）及其受体Fas（APO-1，CD-95）的显著上调精确一致; 2）Fas和FasL均免疫定位于肺泡II型细胞; 3）胎儿和出生后II型细胞对直接Fas激活有反应。 这些结果支持我们的中心假设：Fas/FasL介导的肺泡II型细胞凋亡是一个重要的和发育调节的事件在围产期肺重塑。基于这一假设，我们制定了以下具体目标。在目的1和2中，我们将确定缺氧和机械扩张/拉伸对Fas/FasL信号传导和围产期小鼠II型细胞凋亡的影响。在目的3中，我们将研究II型细胞靶向的四环素调节的FasL过表达在小鼠中对围产期II型细胞凋亡，肺重塑和替代凋亡信号通路的表达的影响。我们预计，阐明围产期II型细胞凋亡的分子机制，将导致对肺的发育生物学的重要见解，并将导致识别新的目标，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.