Transcriptional Programming of Asthma Related Pathology in Respiratory Epithelia

呼吸道上皮细胞中哮喘相关病理学的转录编程

• 批准号: 8228191
• 负责人: Jeffrey A Whitsett
• 金额: $ 51.43万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8228191
• 关键词: Adult; Affect; Allergens; Allergic; Allergic inflammation; Asthma; Automobile Driving; Biochemistry; Bioinformatics; Cell Differentiation process; Cellular biology; Characteristics; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; Cystic Fibrosis; Data; Development; Diagnosis; Epithelial; Epithelial Cells; Family member; Funding; Gene Deletion; Gene Expression; Gene Targeting; Genes; Goblet Cells; Health; Histology; Homeostasis; Host Defense; Hyperactive behavior; Hyperplasia; Immune response; In Vitro; Inflammation; Interleukin-13; Link; Lung; Lung Inflammation; Lung diseases; Mediating; Messenger RNA; Microarray Analysis; Modeling; Molecular and Cellular Biology; Morbidity - disease rate; Mus; Ovalbumin; Pathogenesis; Pathology; Pathway interactions; Phenotype; Physiological; Play; Pneumonia; Process; Production; Pulmonary Pathology; Regulation; Respiration Disorders; Respiratory System; Respiratory physiology; Respiratory tract structure; Role; Structure; Structure of respiratory epithelium; Testing; Tissues; Transcriptional Activation; Transcriptional Regulation; Transgenic Mice; Work; age related; airway epithelium; airway remodeling; alveolar epithelium; base; bronchial epithelium; chemokine; cytokine; forkhead protein; in vivo; insight; interest; laser capture microdissection; mortality; mouse model; novel; programs; pulmonary function; respiratory; response; trafficking; transcription factor

DESCRIPTION (provided by applicant): This new application seeks funding to identify and define a transcriptional network that determines Respiratory Epithelial Cell (REC) differentiation, goblet cell hyperplasia, and TH2-like pulmonary phenotypes related to the pathogenesis of asthma and other chronic pulmonary disorders. The application is based on novel data demonstrating the critical roles of a transcriptional network consisting of an Ets family member, SPDEF (SAM pointed domain ets-like factor) and FOXA2 in the regulation of goblet cell differentiation and TH2- like processes in the lung. Our preliminary data demonstrate that differentiation of epithelial cells in conducting airways, is mediated by an intrinsic transcriptional program regulated by FOXA2 and SPDEF that, in turn, drives goblet cell hyperplasia, eosinophilic chemokine, and TH2 cytokine expression from the respiratory epithelium. The application will utilize transgenic mouse models, bioinformatics, in vitro cultures of airway epithelial cells, and biochemistry to determine mechanisms controlling the intrinsic goblet cell program in the lung, and mechanisms by which the respiratory epithelium determines asthma related phenotypes in the mouse lung. Aim 1 will test the hypothesis that the transcription factor FOXA2 plays a critical role in conducting airway epithelial cell differentiation, regulating goblet cell hyperplasia and the expression of genes mediating TH2-like inflammation. Mechanisms by which FOXA2 and FOXA3 differentially regulate gene expression in the respiratory tract will be identified. Aim 2 will test the hypothesis that SPDEF, an ets-like factor, expressed in conducting airways, regulates goblet cell differentiation, in part, via FOXA2. Aim 3 will determine the role of Spdef gene deletion on respiratory epithelial cell differentiation, gene expression, and response to pulmonary allergen and IL-13 challenge, testing the hypothesis that Spdef is required for IL-13/allergen induced goblet cell differentiation. The applicant has had a long-standing interest in study of the cellular and molecular biology of the developing alveolar epithelium, and is recently applying these approaches to the study of conducting airway epithelial cell biology. This application is based on the identification of a novel transcriptional network driving goblet cell hyperplasia and TH2-like inflammation from the respiratory epithelium. These studies will provide insights into the pathogenesis of goblet cell hyperplasia and asthma, and will provide basis for the development of new strategies to diagnose and treat chronic respiratory diseases, including asthma, cystic fibrosis, and chronic obstructive pulmonary disease. PUBLIC HEALTH RELEVANCE: Goblet cell hyperplasia, inflammation, and tissue remodeling accompany common chronic respiratory disorders, including asthma, CF, and COPD. This application seeks to determine the role of a novel transcriptional network, mediated by FOXA2 and SPDEF, that regulates epithelial cell differentiation in the airways that, in turn, influences inflammation and innate host defense associated with these chronic pulmonary disorders. The work will identify mechanisms regulating airway epithelial homeostasis that will provide novel targets to diagnose and influence the pathogenesis of chronic pulmonary diseases affecting the airways.

描述（由申请人提供）：这项新申请寻求资金来识别和定义一个转录网络，该网络确定与哮喘和其他慢性肺部疾病发病机制相关的呼吸道上皮细胞（REC）分化、杯状细胞增生和 TH2 样肺部表型。该应用基于新数据，证明由 Ets 家族成员、SPDEF（SAM 指向结构域 ets 样因子）和 FOXA2 组成的转录网络在调节肺中杯状细胞分化和 TH2 样过程中的关键作用。我们的初步数据表明，传导气道的上皮细胞分化是由 FOXA2 和 SPDEF 调节的内在转录程序介导的，进而驱动呼吸道上皮的杯状细胞增生、嗜酸性趋化因子和 TH2 细胞因子表达。该应用将利用转基因小鼠模型、生物信息学、气道上皮细胞体外培养和生物化学来确定控制肺部内在杯状细胞程序的机制，以及呼吸道上皮决定小鼠肺部哮喘相关表型的机制。目标 1 将检验转录因子 FOXA2 在气道上皮细胞分化、调节杯状细胞增生和介导 TH2 样炎症的基因表达中发挥关键作用的假设。将确定 FOXA2 和 FOXA3 差异调节呼吸道基因表达的机制。目标 2 将检验以下假设：SPDEF（一种在传导气道中表达的 ets 样因子）部分通过 FOXA2 调节杯状细胞分化。目标 3 将确定 Spdef 基因缺失对呼吸道上皮细胞分化、基因表达以及对肺部过敏原和 IL-13 攻击的反应的作用，检验 Spdef 是 IL-13/过敏原诱导的杯状细胞分化所必需的假设。申请人长期以来对发育中的肺泡上皮细胞和分子生物学的研究感兴趣，并且最近将这些方法应用于进行气道上皮细胞生物学的研究。该应用基于驱动杯状细胞增生和呼吸道上皮 TH2 样炎症的新型转录网络的鉴定。这些研究将深入了解杯状细胞增生和哮喘的发病机制，并将为开发诊断和治疗慢性呼吸道疾病（包括哮喘、囊性纤维化和慢性阻塞性肺病）的新策略提供基础。公共卫生相关性：杯状细胞增生、炎症和组织重塑伴随着常见的慢性呼吸系统疾病，包括哮喘、CF 和 COPD。本申请旨在确定由 FOXA2 和 SPDEF 介导的新型转录网络的作用，该网络调节气道中的上皮细胞分化，进而影响与这些慢性肺部疾病相关的炎症和先天宿主防御。这项工作将确定调节气道上皮稳态的机制，这将为诊断和影响影响气道的慢性肺部疾病的发病机制提供新的靶点。