Regulation and role of CEACAM6 in the lung alveolus

CEACAM6 在肺泡中的调节和作用

• 批准号: 7742998
• 负责人: PHILIP L. BALLARD
• 金额: $ 38.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-10 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7742998
• 关键词: Address; Adenoviruses; Adult; Alveolar; Alveolus; Antibodies; Apoptosis; Area; Aspirate substance; Bacteria; Binding; Biology; CEA Family Protein; Candidate Disease Gene; Carcinoembryonic Antigen; Cell Adhesion; Cell Adhesion Molecules; Cell Culture System; Cell Differentiation process; Cell Survival; Cells; Characteristics; Clinical; Clinical Data; Cyclic AMP; DNA Microarray Chip; Data; Development; Dexamethasone; Disease; Dose; Epithelial Cells; Fetal Lung; Gene Expression; Genes; Glucocorticoids; Health; Hormones; Host Defense; Human; Immune; In Vitro; Infant; Infection; Inflammation Mediators; Intestinal Neoplasms; Investigation; Lung; Lung diseases; Malignant Neoplasms; Mediating; Mediator of activation protein; Membrane; Metabolism; Modeling; Molecular; Mucous Membrane; Pattern; Physiological; Plasma; Premature Infant; Primary Cell Cultures; Principal Investigator; Process; Production; Property; Protein Biosynthesis; Protein Family; Proteins; Publications; Pulmonary alveolar structure; Recombinants; Regulation; Research; Research Personnel; Role; Sampling; Signal Transduction; Signaling Molecule; Small Interfering RNA; Structure of parenchyma of lung; Surveys; Testing; Time; Tissues; Transcript; Transcriptional Activation; Transfection; Tumor Markers; Type II Epithelial Receptor Cell; Undifferentiated; Update; Western Blotting; alveolar epithelium; alveolar lamellar body; base; cell type; crosslink; density; experience; fetal; hormone regulation; immunoregulation; in vivo; insight; loss of function; lung development; lung injury; novel; postnatal; programs; promoter; protein function; public health research; repository; research study; response; surfactant; thyroid transcription factor 1; transcription factor

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.

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，在多种组织粘膜的先天宿主防御中发挥作用，但是之前没有对其进行详细研究。 CEACAM 位于肺部。我们最初将 CEACAM6 鉴定为人类胎儿肺上皮细胞中的诱导基因，该细胞经历激素刺激分化为 II 型细胞。初步研究表明，CEACAM6 在体内肺发育过程中受到发育调节，并由糖皮质激素和 cAMP 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）的过程协同诱导。此外，CEACAM6 存在于婴儿和成人的气管抽吸物中，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，该项目的首要假设是 CEACAM6 是一种 TTF-1 依赖性 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的 CEACAM6 功能。基础研究利用了特征明确的原代人类细胞培养系统，该系统是与人类肺部发育和疾病高度相关的模型。目标 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。目标 2 将研究激素诱导的人 II 型细胞体外分化过程中 CEACAM6 表达增加的分子介质和机制，表征 TTF-1 和其他介质因子的作用以及与 CEACAM6 启动子的相互作用。目标 3 的实验将利用大量临床样本和临床数据，确定人胎儿肺中 CEACAM6 表达的发育模式和调节机制，并检查肺组织、气管吸出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：这项研究涉及一种先前未开发的肺蛋白 (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。该项目的研究将检查该蛋白在正常肺中的表达和功能及其在应对肺损伤和感染中的作用。