Transcriptional Control of Submucosal Gland Formation and Function

粘膜下腺形成和功能的转录控制

• 批准号: 8152823
• 负责人: Jeffrey A Whitsett
• 金额: $ 39.32万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8152823
• 关键词: Affect; Area; Asthma; Bacteria; Biology; Bronchi; Bronchiectasis; Cell Differentiation process; Cell Line; Chronic Obstructive Airway Disease; Chronic lung disease; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Defect; Development; Disease; Electrolytes; Embryo; Epithelial; Epithelial Cells; Escalator; Family suidae; Gene Expression; Genes; Gland; Grant; Growth; Health; Host Defense; Human; In Vitro; Individual; Infection; Inflammation; Life; Liquid substance; Lung; Lung diseases; Metaplasia; Molecular; Morphogenesis; Mucociliary Clearance; Mucous body substance; Mus; Mutation; NKX2H gene; Pathogenesis; Pattern; Perinatal; Play; Predisposition; Process; Processed Genes; Production; Proteins; Pulmonary Cystic Fibrosis; Recurrence; Regulation; Regulatory Pathway; Research; Respiration Disorders; Respiratory System; Respiratory physiology; Respiratory tract structure; Role; SCID Mice; Site; Sterility; Structure; Surface; System; Testing; Trachea; Transcriptional Regulation; Transgenic Mice; Virus; Work; airway epithelium; base; cell growth; disability; in vivo; microbial; millimeter; mortality; neglect; novel; particle; pathogen; progenitor; programs; promoter; respiratory; toxicant; transcription factor

DESCRIPTION (provided by applicant): The respiratory tract is constantly exposed to microbial pathogens and particles, but is protected by a multitiered host defense system that serves to maintain lung function and sterility. Severe defects in mucociliary clearance, mucus production, and host defense accompany common chronic lung diseases, including cystic fibrosis (CF), chronic obstructive pulmonary disease, and asthma. These disorders are complicated by mucus metaplasia, mucus hyperproduction or inspissation, inflammation, and susceptibility to pulmonary infection. This application seeks to determine the molecular mechanisms underlying deficits in mucociliary clearance associated with pulmonary disease in CF. The work is based on preliminary data demonstrating 1) a novel network of transcription factors that determines both the patterning and differentiation of airway epithelial cells (AECs) lining the developing trachea and bronchi, and the formation of submucosal glands (SMGs) that secrete the majority of fluids, electrolytes, and host defense proteins onto the airway surface and 2) that patterning, growth, diferentiation, and gene expression of AECs and SMGs are influenced by the lack of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). This application will test the hypothesis that PAX9 and an associated transcriptional network play a critical role in the regulation of AEC and SMG morphogenesis and function in the developing and mature airway. This proposal will utilize transgenic mice in which PAX9 and genes associated with PAX9 are conditionally deleted or added to the developing and mature airway epithelium in vivo and in vitro. The molecular and cellular mechanisms by which PAX9 and associated proteins regulate genes and processes critical for AEC and SMG formation and function wil be assessed. The role of the proposed PAX9-dependent regulatory program in the pathogenesis of the pulmonary complications of CF will be determined in CFTR-deficient pigs and mice. This proposal seeks to determine the cellular and molecular basis underlying AEC and SMG morphogenesis and function relevant to the pathogenesis of recurrent infections caused by defects in mucociliary clearance. PUBLIC HEALTH RELEVANCE: Throughout life, the lung is exposed to particles, bacteria, viruses, and other microbial pathogens and toxicants that must be removed from the lung by a mucociliary "escalator." Common, chronic lung diseases, including asthma, chronic obstructive lung disease, and cystic fibrosis (CF) are complicated by mucus hyperproduction and recurrent lung infections, leading to long-term disability and mortality affecting millions of individuals world- wide. This application will identify the mechanisms regulating submucosal gland differentiation and function leading to abnormal airway mucociliary clearance and infection. The grant will identify the processes controlling gene expression that are associated with abnormal submucosal gland formation and function in CF and that are also relevant to the pathogenesis of chronic lung diseases in general. Understanding the processes controlling airway epithelial and submucosal gland function provides a framework for the development of new therapies for chronic lung diseases.

描述（由申请人提供）：呼吸道持续暴露于微生物病原体和颗粒，但受到多层宿主防御系统的保护，该系统用于维持肺功能和无菌性。粘液纤毛清除、粘液产生和宿主防御的严重缺陷伴随常见的慢性肺部疾病，包括囊性纤维化（CF）、慢性阻塞性肺病和哮喘。这些疾病并发有粘液化生、粘液过度生成或粘液化、炎症和对肺部感染的易感性。本申请旨在确定CF中与肺部疾病相关的粘膜纤毛清除缺陷的分子机制。这项工作是基于初步数据，证明1）一种新的转录因子网络，决定了气道上皮细胞（AEC）内衬发育气管和支气管的图案化和分化，以及粘膜下腺体（SMG）的形成，分泌大部分液体，电解质和宿主防御蛋白到气道表面，2）图案化，生长，分化，囊性纤维化跨膜传导调节因子（Cystic Fibrosis Transmembrane Conductance Regulator，CFTR）的缺乏影响AEC和SMG的基因表达。本申请将测试PAX9和相关转录网络在发育和成熟气道中调节AEC和SMG形态发生和功能中起关键作用的假设。该提议将利用转基因小鼠，其中PAX9和与PAX9相关的基因在体内和体外条件性缺失或添加到发育和成熟的气道上皮中。PAX9和相关蛋白调节对AEC和SMG形成和功能至关重要的基因和过程的分子和细胞机制将被评估。将在CFTR缺陷的猪和小鼠中确定所提出的PAX9依赖性调节程序在CF的肺部并发症的发病机制中的作用。该建议旨在确定AEC和SMG形态发生的细胞和分子基础以及与粘膜纤毛清除缺陷引起的复发性感染的发病机制相关的功能。 公共卫生相关性：在整个生命过程中，肺暴露于颗粒、细菌、病毒和其他微生物病原体和有毒物质，这些物质必须通过粘膜纤毛“自动扶梯”从肺中清除。“常见的慢性肺病，包括哮喘、慢性阻塞性肺病和囊性纤维化（CF），由于粘液过度产生和复发性肺部感染而变得复杂，导致长期残疾和死亡，影响全世界数百万人。这项申请将确定机制，调节粘膜下腺体分化和功能，导致异常气道粘膜纤毛清除和感染。该补助金将确定控制基因表达的过程，这些过程与CF中异常粘膜下腺体形成和功能相关，并且与一般慢性肺部疾病的发病机制相关。了解控制气道上皮和粘膜下腺体功能的过程为慢性肺部疾病的新疗法的开发提供了一个框架。