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Anti-inflammatory role of MUC1 mucin

MUC1粘蛋白的抗炎作用

基本信息

批准号：
7867134
负责人：
KWANG CHUL KIM
金额：
$ 36.41万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
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/7867134
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 Molecules 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 Ovary Pathway interactions Patients Phenotype Phosphatidylinositols Phosphorylation Phosphotransferases Physiological Plasmid Cloning Vector Pneumonia Principal Investigator Production Protein Kinase Pseudomonas aeruginosa Receptor Cross-Talk Role Series Signal Pathway Signal Transduction Site Small Interfering RNA Staging Surface System 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 cytokine enteropeptidase extracellular in vivo inhibitor/antagonist insight 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

Pseiulomonus aeruginosa (PA) is an opportunistic bacterial pathogen responsible for a number of idinically important lung diseases including pneumonia and cystic fibrosis (CF). In the case of CF, .he major j jcause 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 therespiratory system of both normal and CF individuals, "selective"' infection by this pathogen among CF pi.tients suggests the presence of a disease-causing mechanism that is not present in non-CF airways. A number of di ffeivnt theories have been proposed to account for the etiology of CF. Our laboratory made theinteresting observation that MUC1 mucin on the surface of airway epithelial cells is a specific binding site for PA mediated through bacterial flagellin. The structureof 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 preliminarystudies showed that, compared with wild type mice, Mud knockout animals exhibited increased PA clearance from the lungs and greater recruitment of airway leukocytes and higher levels of the proinflammatory cytokincs in bronchoalveolar lavuge fluid following PA flagellin stimulation. Interestingly,TLR5 is another cell surface receptor tha generates an intracellular signaling pathway following binding to flagellin. Based on this similarity, we conducted additional experiments to investigate the functional relationshipbetween 'ViUCl 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 thai MUC1 is an anti- inflamrnatory cell surface receptor that acts, at least in part, through antagonism of flagellin-'1 LR5 signaling. In this proposal, we will test our theory by determining the mechanisms by which MUC1 attenuatesT1..R5 signal transduction. Successful completion of this project will provide important insights for the role of MIJC1 in inflammation, innate immunity, and the early stages of PA infection in CF.

铜绿假单胞菌 (PA) 是一种机会性细菌病原体，可导致许多疾病非常重要的肺部疾病，包括肺炎和囊性纤维化（CF）。就 CF 而言，.he 大调 j j 受影响患者发病率和死亡率的原因是由于粘稠物的存在而导致气道阻塞顽强的粘液会严重感染 PA。因为 PA 暴露发生在呼吸道正常人和 CF 个体的系统中，这种病原体在 CF 患者中的“选择性”感染表明存在非 CF 气道中不存在的致病机制。一些不同的已经提出了一些理论来解释 CF 的病因。我们的实验室让事情变得有趣观察气道上皮细胞表面的MUC1粘蛋白是PA的特异性结合位点通过细菌鞭毛蛋白介导。 MUC1 糖蛋白的结构表明它充当与鞭毛蛋白相互作用后在细胞内传递信号的受体。利用小鼠基因经过修饰以阻断 MUC1 表达（MUC1 敲除小鼠），我们的初步研究表明，相比与野生型小鼠相比，Mud 敲除动物表现出肺部 PA 清除率增加，并且支气管肺泡中气道白细胞的募集和促炎细胞因子的升高 PA 鞭毛蛋白刺激后灌洗液。有趣的是，TLR5 是另一种细胞表面受体与鞭毛蛋白结合后产生细胞内信号传导途径。基于这种相似性，我们进行了额外的实验来研究'ViUC1和TLR5之间的功能关系。我们观察到 MUC1 的表达抑制正常肺细胞中的鞭毛蛋白-TLR5 信号通路，但不是 CF 气道上皮细胞。基于这些结果，我们假设 MUC1 是一种抗炎症细胞表面受体，至少部分通过拮抗鞭毛蛋白-'1 LR5 信号传导发挥作用。在本提案中，我们将通过确定 MUC1 衰减 T1..R5 的机制来测试我们的理论信号转导。该项目的成功完成将为我们的作用提供重要的见解。 MIJC1 在炎症、先天免疫和 CF 中 PA 感染的早期阶段中的作用。