Role of MUC5AC Mucins in Airway Disease

MUC5AC 粘蛋白在气道疾病中的作用

基本信息

批准号：
7795099
负责人：
Mary C Rose
金额：
$ 33.2万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-03-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7795099
关键词：
A549 Acetylation Acute Adrenal Cortex Hormones Anti-Inflammatory Agents Asthma Binding Bronchitis Bronchopulmonary Dysplasia CREB1 gene Cells Chromatin Chromatin Structure Chronic Obstructive Airway Disease Chronic lung disease Complex Cystic Fibrosis DNA Polymerase II Data Dexamethasone Disease EGF gene Epithelial Cells Equilibrium Event Exhibits Extrinsic asthma Figs - dietary Foundations Gene Expression Gene Expression Regulation Genes Genetic Transcription Glucocorticoids Glycoproteins Goblet Cells Histone Acetylation Histone H4 Histones Human Hyperplasia In Vitro Indium Inflammation Mediators Inflammatory Interleukin-1 Left Link Lung Lung diseases MUC5AC gene Maintenance Mediating Mediator of activation protein Messenger RNA Metaplasia Modeling Modification Molecular Morbidity - disease rate Mucins Mucous body substance Mus Nucleosomes Obstruction Pathway interactions Patients Pharmacologic Substance Phosphorylation Production RNA Recruitment Activity Repression Resolution Respiratory System Respiratory tract structure Role SP1 gene Severities Site Steroids Stimulus Structure of parenchyma of lung TNF gene Testing Therapeutic Intervention Transcript Up-Regulation activating transcription factor airway epithelium asthmatic airway asthmatic patient base chromatin modification chromatin remodeling human tissue in vivo in vivo Model mortality novel overexpression promoter public health relevance transcription factor

项目摘要

DESCRIPTION (provided by applicant): Secretory mucin glycoproteins are the major macromolecular component of lung mucus, which coats and protects the respiratory tract. Mucins are hypersecreted and overproduced in acute and chronic lung disease, thereby contributing to mucus obstruction in the airways and to disease morbidity and mortality in patients with asthma and other chronic obstructive pulmonary diseases. MUC5AC, one of the major airway mucins, is localized to goblet cells in the conducting airway epithelium, and is overexpressed in asthmatic airways. Our long term objective is to better define the link between activation and repression of MUC5AC mucin gene expression at the molecular level in order to provide a better foundation for developing novel pharmaceutical agents to circumvent mucin overproduction. The MUC5AC gene can be transcriptionally activated (IL-1¿) or repressed (Dex) in lung cells in a pathologically and pharmacologically relevant fashion. However, little is known about mechanisms that regulate mucin gene cis-repression, which likely involve remodeling of chromatin, a higher level of gene regulation, or about chromatin modification of mucin genes. In this application, we will focus on Dex-mediated chromatin remodeling in cis- repression of MUC5AC gene expression and on IL-1¿-induced chromatin modifications in upregulating MUC5AC gene expression. We will investigate mechanisms underlying these events in lung cells in three Aims. They will be evaluated in vitro in differentiated NHBE cells and A549 cells and in vivo in a murine model of allergic asthma and in human tissue. In Aim 1 we will characterize the GR-induced cis-repression of MUC5AC at the chromatin level to test the hypothesis that Dex cis-represses MUC5AC gene expression by chromatin remodeling. In Aim 2 we will characterize the IL-1¿-induced activation of the MUC5AC gene to test the hypothesis that the MUC5AC gene belongs to a class of genes with promoters with regulated and late accessibility, e.g. promoters that require stimulus-dependent modifications in chromatin structure to make transcription factors sites accessible for transcription. In Aim 3 we will determine whether inflammatory mediators (IL-1¿) and anti-inflammatory agents (Dex) mediate opposing effects on MUC5AC chromatin structure in lung cells exposed to both mediators. This would ultimately impact on MUC5AC mucin production during corticosteroid treatment of inflammatory lung disease. PUBLIC HEALTH RELEVANCE. Mucins are hypersecreted and overproduced in chronic lung disease, thereby contributing to mucus obstruction in the airways and to disease morbidity and mortality in patients with asthma and other chronic obstructive pulmonary diseases. MUC5AC is a major lung mucin and is overproduced in asthmatic airways. The MUC5AC gene has been shown to be transcriptionally activated (IL-1¿) or repressed (Dex) in lung cells in a pathologically and pharmacologically relevant fashion. Understanding the mechanisms whereby MUC5AC gene expression is repressed by glucocorticoids will prove useful in understanding why steroid maintenance is important in reducing the number and severity of exacerbations in severe asthmatic patients and is fundamental for formulating therapeutic interventions in lung diseases with mucin overproduction.

描述（由适用提供）：秘密粘蛋白糖蛋白是肺粘液的主要大分子成分，肺粘液涂层和保护呼吸道。粘蛋白在急性和慢性肺部疾病中脱粒和产生过多，从而导致哮喘和其他慢性阻塞性肺部疾病患者的气道粘液阻塞以及疾病的发病率和死亡率。 MUC5AC是主要气道粘蛋白之一，被定位为导电道上皮的杯状细胞，并在哮喘气道中过表达。我们的长期目标是更好地定义MUC5AC粘蛋白基因表达在分子水平上的激活与表达之间的联系，以便为开发新型药物以绕过粘蛋白过量产生的生产提供更好的基础。 MUC5AC基因可以以病理和药理相关的方式在肺细胞中转录激活（IL-1？）或反射（DEX）。然而，对于调节粘蛋白基因顺序抑制的机制知之甚少，这些机制可能涉及染色质的重塑，较高的基因调节水平或粘蛋白基因的染色质修饰。在此应用中，我们将重点介绍MUC5AC基因表达的顺式抑制中DEX介导的染色质重塑，以及在上调MUC5AC基因表达中的IL-1？诱导的染色质修饰。我们将研究三个目标中肺部细胞中这些事件的基础机制。它们将在分化的NHBE细胞和A549细胞以及体内在体外进行评估，在过敏性哮喘和人体组织中的鼠模型中。在AIM 1中，我们将表征MUC5AC在染色质水平上的GR诱导的顺式抑制，以检验以下假设：DEX顺式抑制通过染色质重塑可抑制MUC5AC基因的表达。在AIM 2中，我们将表征IL -1？诱导的MUC5AC基因的激活，以检验MUC5AC基因属于具有启动子具有调节且可及性的启动子的一类基因的假设，例如需要在染色质结构中进行刺激依赖性修饰的启动子使转录因子位点可访问进行转录。在AIM 3中，我们将确定炎症介质（IL-1？）和抗炎剂（DEX）是否对暴露于两个介质的肺部细胞中MUC5AC年结构的影响是否相反。这最终将影响炎性肺疾病的皮质类固醇治疗期间对粘液5ac粘蛋白的产生。公共卫生相关性。粘蛋白在慢性肺部疾病中是超霉素和过量的，从而导致气道粘液阻塞，以及哮喘和其他慢性阻塞性肺部疾病患者的疾病发病率和死亡率。 MUC5AC是一种主要的肺粘蛋白，在哮喘气道中产生过多。 MUC5AC基因已被证明是在肺细胞中以病理和药物相关的方式在肺细胞中反射的转录激活（IL-1？）。了解糖皮质激素反映MUC5AC基因表达的机制将被证明可用于理解为什么立体素维持在减少严重哮喘患者中恶化的数量和严重程度很重要，并且对于在肺部疾病中制定治疗性疾病的治疗性疾病的基础是基础。