Anti-inflammatory role of MUC1 mucin

MUC1粘蛋白的抗炎作用

• 批准号: 7337290
• 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
• 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/7337290
• 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; 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; human TNF protein; 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

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（Pseiulomonus aeruginosa，PA）是一种机会性细菌病原体，其引起许多细菌感染。 重要的肺部疾病，包括肺炎和囊性纤维化（CF）。在CF的情况下，他主要是j 在患病患者中发病率和死亡率的原因是由于存在厚的 以及被PA严重感染的粘性粘液。因为PA暴露发生在呼吸道 系统的正常和CF个人，“选择性”感染的这种病原体之间CF的tients建议 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。我们的实验室使这个有趣的 气道上皮细胞表面粘蛋白MUC 1是PA的特异性结合位点 通过细菌鞭毛蛋白介导。MUC 1糖蛋白的结构表明，它作为一种 受体在与鞭毛蛋白相互作用后在细胞内传递信号。利用老鼠的基因 我们的实验性研究表明， 对于野生型小鼠，Mud敲除动物表现出肺PA清除率增加， 呼吸道白细胞的募集和支气管肺泡中促炎性因子水平的升高 PA鞭毛蛋白刺激后的冲洗液。有趣的是，TLR 5是另一种细胞表面受体， 在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 进行了额外的实验以研究ViUCl和TLR 5之间的功能关系。我们 观察到MUC 1的表达抑制了正常肺细胞中鞭毛蛋白-TLR 5信号通路， 而不是CF气道上皮细胞。基于这些结果，我们形成了MUC 1是抗- 炎性细胞表面受体，其至少部分地通过鞭毛蛋白-1LR5信号传导的拮抗作用起作用。 在这个提议中，我们将通过确定MUC 1衰减T1的机制来测试我们的理论。R5 信号转导该项目的成功完成将为以下方面的作用提供重要见解： MIJC 1在CF的炎症、先天免疫和PA感染的早期阶段中的作用