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）：呼吸道不断暴露于微生物病原体和颗粒中，但受到多层宿主防御系统的保护，该系统可维持肺功能和无菌性。常见的慢性肺部疾病（包括囊性纤维化（CF），慢性阻塞性肺部疾病和哮喘），粘膜钙清除，粘液产生和宿主防御的严重缺陷伴随着常见的慢性肺部疾病。这些疾病因粘液化生，粘液过多产生或引发，炎症以及对肺部感染的敏感性而变得复杂。该应用旨在确定与CF中肺部疾病相关的粘膜钙清除率缺陷的分子机制。这项工作基于初步数据，证明1）一个新的转录因子网络，该网络决定了气道上皮细胞（AEC）的模式和差异化，而在发展中的气管和支气管中，粘膜粘膜（SMG）的形成（SMGS）的形成使液体，电动蛋白的大量表现出来，并构成了抗抗性的蛋白质，并构成了差异，并差异化。 AEC和SMG的影响受囊性纤维化跨膜电导调节剂（CFTR）的影响。该应用将检验以下假设：PAX9和相关的转录网络在调节AEC和SMG形态发生以及在发育和成熟气道中的功能中起关键作用。该建议将利用转基因小鼠，其中PAX9和与PAX9相关的基因被条件删除或添加到体内和体外的发育中和成熟的气道上皮。将评估PAX9和相关蛋白调节基因和过程对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。拟议的PAX9依赖性调节程序在CF的肺部并发症的发病机理中的作用将在CFTR缺乏的猪和小鼠中确定。该提案旨在确定AEC的细胞和分子基础和SMG形态发生以及与粘膜切除率缺陷引起的复发感染的发病机理相关的功能。 公共卫生相关性：在整个生命中，肺部暴露于颗粒，细菌，病毒和其他微生物病原体和毒物中，这些病原体和毒物必须由粘膜胶体“自动扶梯”从肺部清除。常见的慢性肺疾病，包括哮喘，慢性阻塞性肺部疾病和囊性纤维化（CF），粘液高生产和复发性肺部感染使人复杂，导致长期残疾和死亡率影响数百万个个体。该应用将确定调节粘膜粘膜分化和功能的机制，从而导致气道粘膜切除率和感染异常。该赠款将确定控制基因表达的过程，这些过程与CF中异常的粘膜腺体形成和功能相关，这也与一般的慢性肺部疾病的发病机理有关。了解控制气道上皮和粘膜粘膜功能的过程为开发慢性肺部疾病的新疗法提供了一个框架。