Anti-inflammatory role of MUC1 mucin

MUC1粘蛋白的抗炎作用

基本信息

批准号：
7175473
负责人：
KWANG CHUL KIM
金额：
$ 49.76万
依托单位：
LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-02-03 至 2010-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7175473
关键词：
Abbreviations Accounting Adaptor Signaling Protein Agrin Air Anti-Inflammatory Agents Anti-inflammatory Attenuated Binding Binding Proteins Binding Sites Boxing Bronchoalveolar Lavage Bronchoalveolar Lavage Fluid Cell Differentiation process Cell Surface Receptors Cells Chimeric Proteins Chinese Hamster Ovary Cell Co-Immunoprecipitations Cystic Fibrosis Cytoplasmic Tail Deletion Mutagenesis Disease Dominant-Negative Mutation E-Selectin EGF gene Engineering Epidermal Growth Factor Receptor Epithelial Epithelial Cells Etiology Exhibits Extracellular Domain Extracellular Signal Regulated Kinases Far-Western Blotting Flagella Flagellin Glycoproteins Gray unit of radiation dose Growth Factor Hamsters IL8 gene Immunoprecipitation Individual Infection Inflammation Kinetics Knock-out Knockout Mice Label Laboratories Leukocyte-Adhesion Receptors Leukocytes Liquid substance Lung Lung diseases MEKs Mediating Methods Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Mitogens Monitor Morbidity - disease rate Mucin-1 Staining Method Mucins Mucous body substance Mus Mutagenesis Natural Immunity Numbers Ovary Pathway interactions Patients Phenotype Phosphatidylinositols Phosphorylation Phosphotransferases Physiological Plasmid Cloning Vector Pneumonia Principal Investigator Production Protein Kinase Pseudomonas aeruginosa Receptor Cross-Talk Respiratory System Role Series Signal Pathway Signal Transduction Site Small Interfering RNA Staging Structure Surface TLR5 gene Tandem Repeat Sequences Testing Thick Toll-like receptors Transfection Tumor Necrosis Factor-alpha Tumor Necrosis Factors Wild Type Mouse airway obstruction base cancer cell cystic fibrosis airway cystic fibrosis patients cytokine enteropeptidase extracellular human TNF protein in vivo inhibitor/antagonist insight interest knockout animal macrophage mortality mutant neutrophil novel pathogen programs receptor research study response sperm protein stress activated protein kinase stress-activated protein kinase 1 theories

项目摘要

DESCRIPTION (provided by applicant): Pseudomonas aeruginosa (PA) is an opportunistic bacterial pathogen responsible for a number of clinically important lung diseases including pneumonia and cystic fibrosis (CF). In the case of CF, the major cause of morbidity and mortality among afflicted patients is airway obstruction due to the presence of thick and tenacious mucus that becomes heavily infected with PA. Because PA exposure occurs in the respiratory system of both normal and CF individuals, "selective"' infection by this pathogen among CF patients suggests the presence of a disease-causing mechanism that is not present in non-CF airways. A number of different theories have been proposed to account for the etiology of CF. Our laboratory made the interesting observation that MUC1 mucin on the surface of airway epithelial cells is a specific binding site for PA mediated through bacterial flagellin. The structure of the MUC1 glycoprotein suggests that it acts as a receptor to transmit signals intracellularly following interaction with flagellin. Using mice genetically modified to block MUC1 expression (MUC1 knockout mice), our preliminary studies showed that, compared with wild type mice, Muc1 knockout animals exhibited increased PA clearance from the lungs and greater recruitment of airway leukocytes and higher levels of the proinflammatory cytokines in bronchoalveolar lavage fluid following PA flagellin stimulation. Interestingly, TLR5 is another cell surface receptor that generates an intracellular signaling pathway following binding to flagellin. Based on this similarity, we conducted additional experiments to investigate the functional relationship between MUC1 and TLR5. We observed that expression of MUC1 inhibited the flagellin-TLR5 signaling pathway in normal lung cells but not CF airway epithelial cells. Based on these results, we formed the hypothesis that MUC1 is an anti-inflammatory cell surface receptor that acts, at least in part, through antagonism of flagellin-TLR5 signaling. In this proposal, we will test our theory by determining the mechanisms by which MUC1 attenuates TLR5 signal transduction. Successful completion of this project will provide important insights for the role of MUC1 in inflammation, innate immunity, and the early stages of PA infection in CF.

描述（由申请人提供）：铜绿假单胞菌（PA）是一种机会性细菌病原体，负责许多临床上重要的肺部疾病，包括肺炎和囊性纤维化（CF）。就CF而言，受伤患者发病率和死亡率的主要原因是由于存在厚而顽强的粘液而导致气道障碍物受到PA的大量感染。由于PA暴露发生在正常和CF个体的呼吸系统中，因此CF患者中这种病原体的“选择性”感染表明存在非CF气道中不存在的引起疾病的机制。已经提出了许多不同的理论来说明CF的病因。我们的实验室提出了一个有趣的观察结果，即气道上皮细胞表面上的粘液粘蛋白是通过细菌鞭毛蛋白介导的PA的特定结合位点。 MUC1糖蛋白的结构表明，它是与鞭毛蛋白相互作用后细胞内传输信号的受体。使用基因修饰以阻断MUC1表达（MUC1基因敲除小鼠）的小鼠，我们的初步研究表明，与野生型小鼠相比，MUC1敲除动物表现出肺部肺白细胞的PA清除率增加，并且在Bronchoalaalve aLavage pa pa pa lotid pa的肺白细胞和较高水平的促进性细胞因子的募集量更高。有趣的是，TLR5是另一个细胞表面受体，它与鞭毛蛋白结合后会产生细胞内信号通路。基于这种相似性，我们进行了其他实验，以研究MUC1和TLR5之间的功能关系。我们观察到MUC1的表达抑制了正常肺部细胞中的鞭毛蛋白-TLR5信号通路，但不能抑制CF气道上皮细胞。基于这些结果，我们形成了以下假设：MUC1是一种抗炎细胞表面受体，至少部分通过鞭毛蛋白-TLR5信号传导作用。在此提案中，我们将通过确定MUC1减弱TLR5信号转导的机制来测试我们的理论。该项目的成功完成将为MUC1在炎症，先天免疫和PA感染的早期感染中的作用提供重要见解。