Regulation and role of CEACAM6 in the lung alveolus

描述（由申请人提供）：癌胚细胞粘附分子（CEACAM）蛋白家族多年来一直被认为是肠道肿瘤标志物，在几种组织粘膜的先天宿主防御中发挥作用，但此前尚未对肺中的CEACAM进行详细研究。我们最初发现CEACAM6是人胎儿肺上皮细胞在激素刺激下向II型细胞分化的诱导基因。初步研究表明，CEACAM6在体内肺发育过程中受到发育调节，并在糖皮质激素和cAMP的协同诱导下，通过甲状腺转录因子-1 （TTF-1）这一II型细胞的关键转录因子的作用。此外，CEACAM6在婴儿和成人的气管吸入物中发现，部分与分泌表面活性剂有关，并在肺损伤和感染中上调。基于这些观察结果，本项目的主要假设是CEACAM6是一种ttf -1依赖性的II型细胞特异性蛋白，参与肺部先天宿主防御。研究CEACAM6在肺泡中的发育和激素调节以及功能有三个目的。基础研究利用了一个特征良好的原代人类细胞培养系统，这是一个与人类肺部发育和疾病高度相关的模型。Aim 1的研究将探索CEACAM6与表面活性剂的相互作用，以及CEACAM6对II型细胞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将研究体外激素诱导人II型细胞分化过程中CEACAM6表达增加的分子介质和机制，表征TTF-1等介导因子的作用以及与CEACAM6启动子的相互作用。Aim 3的实验将利用大量临床样本和临床数据，确定CEACAM6在人胎儿肺中的表达发育模式和调控机制，并研究出生后肺组织、气管吸入物和血浆中CEACAM6表达水平与早产儿肺部疾病的关系。与公共卫生相关：本研究涉及一种以前未被探索的肺蛋白（CEACAM6），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.