Translational Regulation in Bronchial Epithelial Cells

支气管上皮细胞的翻译调控

• 批准号: 8040856
• 负责人: Ann-Bin Shyu
• 金额: $ 37.92万
• 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/8040856
• 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. PUBLIC HEALTH RELEVANCE: The production of inflammatory mediators by airway epithelium is an important component that contributes to the pathogenesis of airway inflammatory diseases such as asthma. This project is designed to examine novel mechanisms regulating the production of mediators in the airway bronchial epithelium at the post-transcriptional level.

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中炎症反应相关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，是对抗空气中颗粒物、过敏原和感染原的第一道防线。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稳态方面，而且在气道疾病的发病机制中发挥着关键的、多方面的作用。在过敏性气道炎症过程中，上皮细胞既是介质产生的来源，也是重塑过程的靶点。然而，很少有人知道的转录后调节介质，效应和重塑基因的表达在这些细胞在炎症反应，以及如何调节可能会改变时，气道炎症变得持久，如哮喘。我们已经进行了广泛的初步研究，使用原代正常或哮喘的人支气管上皮（HBE）细胞培养在液-气界面，人支气管上皮BEAS-2B细胞，和过敏性气道炎症的体内小鼠模型。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，P体是用于储存和/或降解抑制性mRNA的胞质结构域。这些变化导致蛋白质合成的过度活跃状态，这有助于维持炎症介质的过量产生，从而使哮喘炎症的慢性性质永久化。在本研究中，我们将：1）确定miR-26和miR-16丰度的降低是否有助于在哮喘原代HBE细胞中观察到的IL-6水平的持续升高; 2）确定在哮喘原代HBE细胞中显著下调的一组miRNA在控制支气管上皮细胞中翻译机制的活性中的作用;和3）确定P体的减少是否是活化的支气管上皮细胞的标志，以及P体组装和分解的改变如何影响支气管上皮细胞中的炎症反应。哮喘患者的气道上皮细胞基本上是异常的，但这种异常的分子和生化基础在很大程度上仍不清楚。我们将采用最先进的方法，以获得关键的见解，翻译调节炎症介质的生产和病理机制，这种调节可能会改变支气管上皮细胞在哮喘。拟议的研究涉及气道炎症研究的一个未探索但令人兴奋的新领域，并可能为气道炎症领域引入新的概念和方法。这些结果有可能确定新的靶点，以加速开发与哮喘相关的慢性气道炎症的新治疗方法。 公共卫生关系：气道上皮细胞产生的炎症介质是导致哮喘等气道炎症性疾病发病的重要因素。本项目旨在研究在转录后水平调节气道支气管上皮细胞中介质产生的新机制。