Regulation and role of CEACAM6 in the lung alveolus

描述（由申请方提供）：多年来，已知癌胚细胞粘附分子（CEACAM）蛋白家族作为肠道肿瘤标志物，在几种组织的粘膜中的先天宿主防御中发挥作用，但以前没有对肺中CEACAM的详细研究。我们最初确定CEACAM 6作为诱导基因在人胎儿肺上皮细胞经历的细胞刺激分化为II型细胞。初步研究表明，CEACAM 6在体内肺发育过程中受到发育调控，并通过涉及甲状腺转录因子-1（TTF-1）（II型细胞中的关键转录因子）的过程由糖皮质激素和cAMP协同诱导。此外，CEACAM 6存在于婴儿和成人的气管吸出物中，部分与分泌的表面活性剂相关，并且似乎在肺损伤和感染中上调。基于这些观察结果，该项目的首要假设是CEACAM 6是一种TTF-1依赖的II型细胞特异性蛋白，参与肺先天宿主防御。提出了三个目标来研究发育和激素调节以及肺泡中CEACAM 6的功能。基础研究利用了一个充分表征的原代人细胞培养系统，该系统是人肺发育和疾病的高度相关模型。目的1的研究将探索CEACAM 6与表面活性剂的相互作用以及CEACAM 6对II型细胞的凋亡和先天免疫特性的影响，使用腺病毒转导和siRNA方法获得和丧失功能。目的2研究CEACAM 6启动子与TTF-1等介导因子的相互作用，探讨CEACAM 6在体外诱导人II型细胞分化过程中表达增强的分子介质和机制。目的3的实验将确定人胎肺中CEACAM 6表达的发育模式和调节机制，并利用大量临床样品和临床数据库检查肺组织、气管抽吸物和血浆中出生后水平与早产儿肺部疾病的关联。与公共卫生的相关性：这项研究解决了以前未探索的肺蛋白（CEACAM 6），该蛋白在与宿主防御和癌症相关的其他组织中具有重要功能。本项目的研究将检测该蛋白在正常肺中的表达和功能，以及其在肺损伤和感染反应中的作用。

DESCRIPTION (provided by applicant): The carcinoembryonic cell adhesion molecule (CEACAM) family of proteins has been known for many years as intestinal tumor markers with a role in innate host defense in mucosa of several tissues, however there have been no previous detailed studies of CEACAMs in the lung. We initially identified CEACAM6 as an induced gene in human fetal lung epithelial cells undergoing hormone-stimulated differentiation into type II cells. Preliminary studies indicate that CEACAM6 is developmentally regulated during in vivo lung development and is induced synergistically by glucocorticoid and cAMP by a process involving thyroid transcription factor-1 (TTF-1), a key transcription factor in type II cells. In addition, CEACAM6 is found in tracheal aspirates of infants and adults, associated in part with secreted surfactant, and appears to be up-regulated in lung injury and infection. Based on these observations, the overriding hypothesis of this project is that CEACAM6 is a TTF-1-dependent, type II cell-specific protein that is involved in lung innate host defense. Three aims are proposed to investigate developmental and hormonal regulation as well as CEACAM6 function in the alveolus. The basic studies utilize a well characterized primary human cell culture system that is a highly relevant model for human lung development and disorders. Studies of Aim 1 will explore CEACAM6 interaction with surfactant and effects of CEACAM6 on apoptosis and innate immune properties of type II cells using adenovirus transduction and siRNA approaches for gain and loss of function. Aim 2 will investigate molecular mediators and mechanisms for increased expression of CEACAM6 during hormone-induced differentiation of human type II cells in vitro, characterizing the role of TTF-1 and other mediating factors and interactions with CEACAM6 promoter. Experiments of Aim 3 will determine the developmental pattern and regulatory mechanisms of CEACAM6 expression in human fetal lung and examine associations of postnatal levels in lung tissue, tracheal aspirates and plasma with lung disease of premature infants, utilizing a large repository of clinical samples and clinical data. Relevance to Public Health: This research addresses a previously unexplored lung protein (CEACAM6) that has important functions in other tissues related to host defense and cancer. The studies of this project will examine expression and function of the protein in normal lung and its role in response to lung injury and infection.