权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Translational Regulation in Bronchial Epithelial Cells

支气管上皮细胞的翻译调控

基本信息

批准号：
7929075
负责人：
Ann-Bin Shyu
金额：
$ 37.5万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-23 至 2011-07-24
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7929075
关键词：
Air Airborne Particulate Matter Allergens Allergic Antigens Asthma Attenuated Binding Proteins Biochemical CCL2 gene Cell Culture Techniques Cell Nucleus Cell model Cells Chemicals Chronic Chronic Obstructive Airway Disease Code Collagen Gene Complex Cytoplasm Cytoplasmic Tail Data Dendritic Cells Development Disease Elements Environment Epithelial Epithelial Cells Exposure to Feedback Gene Expression Genes Health Homeostasis Human IL8 gene Immune response Immunity In Vitro Indium Infectious Agent Inflammation Inflammation Mediators Inflammatory Inflammatory Response Interleukin-4 Interleukin-6 Lead Link Liquid substance Lung Inflammation Maintenance Mediating Mediator of activation protein Messenger RNA MicroRNAs Modeling Molecular Participant Pathogenesis Patients Play Post-Transcriptional Regulation Process Production Proteins RNA RNA Processing Regulation Repression Role Source Testing Th2 Cells Transcriptional Activation Translating Translation Initiation Translational Regulation Translational Repression Translations Untranslated Regions airway epithelium airway inflammation allergic airway inflammation base bronchial epithelium chemokine cytokine design in vivo insight knock-down mRNA Decay mRNA Stability mouse model novel novel therapeutic intervention translation factor

项目摘要

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. During allergic airway inflammation the epithelium is both a source of mediator production as well as a target of remodeling processes. Thus, bronchial epithelial cells play a critical role not only in the maintenance of physico-chemical homoeostasis of the airways but also in the pathogenesis of airway diseases. Yet, little is known about the post-transcriptional regulation of mediator, effector and remodeling gene expression in these cells during the inflammatory response. Using two in vitro cell models and an in vivo mouse model for allergic airway inflammation, our preliminary studies support the following model: Upon IL-4/TNF-α stimulation, transcriptional activation results in an influx of inflammatory mediator mRNAs into the cytoplasm, where microRNA (miRNA)-mediated translation repression is released, global translation increases, and P-bodies (cytoplasmic domains for storage and/or degradation of translationally repressed mRNAs) disassembled. These concerted post-transcriptional activities help the cell deal with a rapid demand for translating inflammatory mediator mRNAs into proteins. After a persistent exposure to IL-4/TNF-α, translocation of HuR, an AU-rich element (ARE) binding protein, from the nucleus to the cytoplasm is elicited in activated bronchial epithelial cells. HuR then associates with cytoplasmic ARE-containing mRNAs coding for inflammatory mediators to down-regulate their translation, thereby dampening the inflammatory response. The following specific aims are designed to test this model: 1) To elucidate the molecular and biochemical mechanisms that alter the function of miR-155, an miRNA closely linked to immunity, in activated bronchial epithelial cells and to define the role of miR-155 in regulating inflammatory mediator gene expression in bronchial epithelial cells; 2) To 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 responses in bronchial epithelial cells; and 3) To determine how HuR down-regulates the expression of inflammatory mediator molecules such as MCP-1 in activated bronchial epithelial cells and how altering HuR expression in bronchial epithelium modulates allergic airway inflammation. The proposed studies will provide important mechanistic insights into the post-transcriptional mechanisms operating in bronchial epithelial cells to regulate their inflammatory responses, thereby leading to the development of new therapeutic approaches to alleviate airway inflammation associated with chronic airway diseases such as asthma and chronic obstructive pulmonary diseases (COPD).

支气管的上皮细胞直接暴露在环境中，是第一个