Translational Regulation in Bronchial Epithelial Cells

支气管上皮细胞的翻译调控

• 批准号: 8486371
• 负责人: Ann-Bin Shyu
• 金额: $ 35.72万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-25 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8486371
• 关键词: 3' Untranslated Regions; Affect; Air; Airborne Particulate Matter; Allergens; Area; Asthma; Biochemical; Cell Culture Techniques; Cells; Chemicals; Chronic; Code; Cytoplasmic Tail; Development; Disease; Environment; Epithelial; Epithelial Cells; Gene Expression; Homeostasis; Human; Infectious Agent; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-6; Lead; Link; Liquid substance; Maintenance; Mediating; Mediator of activation protein; Messenger RNA; Methodology; MicroRNAs; Molecular; Mutagenesis; Nature; Pathogenesis; Pathway interactions; Play; Porifera; Post-Transcriptional Regulation; Process; Production; Protein Biosynthesis; Proteins; RNA Processing; Regulation; Research; Role; Site; Source; Speed; Stress; Translational Regulation; Translations; airway epithelium; airway inflammation; allergic airway inflammation; asthmatic patient; base; bronchial epithelium; design; in vivo; insight; mouse model; novel; novel therapeutic intervention; repaired; research study; translation factor

DESCRIPTION (provided by applicant): The objective of this proposal is to elucidate the post-transcriptional mechanisms controlling translation and subcellular localization of mRNAs involved in inflammatory responses in bronchial epithelial cells. Epithelial cells of the bronchial airways are directly exposed to the environment and are the first line of defense against airborne particulate matter, allergens and infectious agents. Mounting evidence suggests that bronchial epithelial cells play a pivotal, multifaceted role not only in the maintenance of physico-chemical homoeostasis of the airways but also in the pathogenesis of airway diseases. During allergic airway inflammation, the epithelium is both a source of mediator production as well as a target of remodeling processes. Yet, little is known about post-transcriptional regulation of mediator, effector and remodeling gene expression in these cells during the inflammatory response, and about how this regulation may be altered when airway inflammation becomes persistent, such as in asthma. We have carried out extensive preliminary studies using primary normal or asthmatic human bronchial epithelial (HBE) cells cultured at the liquid-air interface, human bronchial epithelial BEAS-2B cells, and an in vivo mouse model of allergic airway inflammation. The results suggest that bronchial epithelial cells from asthmatics undergo a coordinated alteration of miRNA profile/function and of P- bodies, cytoplasmic domains for storage and/or degradation of translationally repressed mRNAs. These changes lead to a hyperactive state of the protein synthesis that contributes to sustaining excess production of inflammatory mediators and thus perpetuating the chronic nature of asthmatic inflammation. In the proposed study we will: 1) Determine whether a reduction in miR-26 and miR-16 abundance contributes to the persistent, elevated level of IL-6 observed in asthmatic primary HBE cells; 2) Define the role of a group of miRNAs that are significantly down-regulated in asthmatic primary HBE cells in controlling the activity of translation machinery in bronchial epithelial cells; and 3) Determine whether a reduction in P-bodies is a hallmark of activated bronchial epithelial cells, and how alteration of P-body assembly and disassembly influences the inflammatory response in bronchial epithelial cells. The airway epithelium is fundamentally abnormal in asthma, but the molecular and biochemical bases for this abnormality remains largely undefined. We will employ state-of-the-art approaches to gain critical insights into translational regulation of inflammatory mediator production and the pathological mechanism by which this regulation may be altered in bronchial epithelial cells in asthma. The proposed studies involve an unexplored but exciting new area of research in airway inflammation and are likely to introduce novel concepts and methodologies to the field of airway inflammation. The results have a potential for identifying new targets to speed development of new therapeutic approaches to the chronic airway inflammation associated with asthma.

描述（由申请人提供）：本提案的目的是阐明控制支气管上皮细胞炎症反应中mrna翻译和亚细胞定位的转录后机制。支气管气道的上皮细胞直接暴露于环境中，是抵御空气中颗粒物、过敏原和感染因子的第一道防线。越来越多的证据表明，支气管上皮细胞不仅在维持气道的物理化学平衡中起着关键的、多方面的作用，而且在气道疾病的发病机制中也起着重要作用。在过敏性气道炎症过程中，上皮既是介质产生的来源，也是重塑过程的目标。然而，在炎症反应期间，这些细胞中介质、效应物和重塑基因表达的转录后调控，以及当气道炎症持续时（如哮喘），这种调控如何改变，我们知之甚少。我们使用在液-气界面培养的原代正常或哮喘人支气管上皮（HBE）细胞、人支气管上皮BEAS-2B细胞和体内小鼠变应性气道炎症模型进行了广泛的初步研究。结果表明，哮喘患者的支气管上皮细胞经历了miRNA谱/功能和P-体的协调改变，胞质结构域用于储存和/或降解翻译抑制的mrna。这些变化导致蛋白质合成的过度活跃状态，有助于维持炎症介质的过量生产，从而使哮喘性炎症的慢性本质永续下去。在拟议的研究中，我们将：1)确定miR-26和miR-16丰度的降低是否有助于哮喘原发HBE细胞中观察到的IL-6水平的持续升高；2)明确哮喘原代HBE细胞中显著下调的一组mirna在控制支气管上皮细胞翻译机制活性中的作用；3)确定p小体的减少是否是支气管上皮细胞活化的标志，以及p小体组装和拆卸的改变如何影响支气管上皮细胞的炎症反应。哮喘患者气道上皮基本异常，但这种异常的分子和生化基础仍未明确。我们将采用最先进的方法来深入了解炎症介质产生的翻译调节以及哮喘支气管上皮细胞中这种调节可能被改变的病理机制。提出的研究涉及一个尚未探索但令人兴奋的气道炎症研究新领域，并可能为气道炎症领域引入新的概念和方法。该结果有可能确定新的靶点，以加速开发新的治疗方法，以治疗与哮喘相关的慢性气道炎症。