Anti-inflammatory role of MUC1 mucin

MUC1粘蛋白的抗炎作用

• 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
• 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

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负责许多