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

铜芯：W

• 批准号: 7720724
• 负责人: MONIQUE E DEPAEPE
• 金额: $ 26.75万
• 依托单位: WOMEN AND INFANTS HOSPITAL-RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-16 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720724
• 关键词: Alveolar; Apoptosis; Apoptotic; Bronchopulmonary Dysplasia; CD95 Antigens; Cell Death; Cells; Computer Retrieval of Information on Scientific Projects Database; Developmental Biology; Event; Funding; Grant; In Vitro; Institution; Lead; Life; Lung; Mechanics; Mediating; Molecular; Mus; Perinatal; Protein Overexpression; Research; Research Personnel; Resources; Signal Pathway; Signal Transduction; Source; Stretching; TNFRSF6 gene; Tetracycline; Tetracyclines; Time; Tumor Necrosis Factor Ligand Superfamily Member 6; Type II Epithelial Receptor Cell; United States National Institutes of Health; Up-Regulation; alveolar type II cell; base; disorder prevention; fetal; in vivo; insight; lung development; novel; postnatal

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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 适应出生后的生活需要发育中的肺的结构和细胞重建的协调。我们以前已经证明，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)细胞死亡调节因子Fas配体(FasL)及其受体Fas(APO-1，CD-95)的显著上调恰好与这些II型细胞的凋亡增加相吻合；2)Fas和FasL均免疫定位于肺泡II型细胞；以及(3)胎儿和出生后的II型细胞对Fas的直接激活有反应。这些结果支持我们的中心假设：Fas/FasL介导的肺泡II型细胞凋亡在围生期肺重塑中是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。在目标1和目标2中，我们将在体外和体内检测高氧和机械扩张/拉伸对围产期小鼠II型细胞Fas/FasL信号转导和细胞凋亡的影响。在目标3中，我们将研究四环素调节的Fas L在小鼠体内的II类细胞靶向过表达对围产期II类细胞凋亡、肺重塑和可选的凋亡信号通路表达的影响。我们预计，阐明调节围产期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，并将导致识别与围产期肺重塑相关疾病的治疗或预防的新靶点，例如新生儿的支气管肺发育不良(慢性肺部疾病)。