ROLE OF MUC1 IN THE GENESIS OF ALLERGIC ASTHMA

MUC1 在过敏性哮喘发生中的作用

• 批准号: 7388434
• 负责人: KWANG CHUL KIM
• 金额: $ 22.5万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7388434
• 关键词: Abbreviations; Affect; Agonist; Allergens; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Asthma; Bacteria; Bacterial Infections; Binding; Breathing; Bromodeoxyuridine; Bronchoalveolar Lavage Fluid; Cell Line; Cell physiology; Cells; Consensus Sequence; Cytoplasmic Tail; Defect; Dendritic Cells; Development; Docking; Epithelial Cells; Exhibits; Exploratory/Developmental Grant; Extrinsic asthma; Flagella; Flagellin; Functional disorder; Glycoproteins; Goblet Cells; Hematopoietic; Human; Hyperplasia; Immune response; In Vitro; Inflammation; Inflammatory; Knockout Mice; Lung; Measures; Mediating; Metaplasia; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mucin-1 Staining Method; Mucins; Mus; Ovalbumin; Phenotype; Play; Pneumonia; Proteins; Pseudomonas aeruginosa; Pulmonary Eosinophilia; Role; Signal Transduction; Sorting - Cell Movement; Structure; Surface; T-Cell Proliferation; Testing; Toll-like receptors; Tyrosine Phosphorylation; airway inflammation; base; cancer cell; cytokine; extracellular; in vivo; insight; interest; intraperitoneal; lymph nodes; macrophage; novel; pathogen; receptor; response; Abbreviations; Affect; Agonist; Allergens; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Asthma; Bacteria; Bacterial Infections; Binding; Breathing; Bromodeoxyuridine; Bronchoalveolar Lavage Fluid; Cell Line; Cell physiology; Cells; Consensus Sequence; Cytoplasmic Tail; Defect; Dendritic Cells; Development; Docking; Epithelial Cells; Exhibits; Exploratory/Developmental Grant; Extrinsic asthma; Flagella; Flagellin; Functional disorder; Glycoproteins; Goblet Cells; Hematopoietic; Human; Hyperplasia; Immune response; In Vitro; Inflammation; Inflammatory; Knockout Mice; Lung; Measures; Mediating; Metaplasia; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mucin-1 Staining Method; Mucins; Mus; Ovalbumin; Phenotype; Play; Pneumonia; Proteins; Pseudomonas aeruginosa; Pulmonary Eosinophilia; Role; Signal Transduction; Sorting - Cell Movement; Structure; Surface; T-Cell Proliferation; Testing; Toll-like receptors; Tyrosine Phosphorylation; airway inflammation; base; cancer cell; cytokine; extracellular; in vivo; insight; interest; intraperitoneal; lymph nodes; macrophage; novel; pathogen; receptor; response

DESCRIPTION (provided by applicant): MUC1 (MUC1 in human and Muc1 in non-humans) is a transmembrane mucin-like glycoprotein highly expressed in various cancer cells and its expression has also been shown in various normal epithelial cells as well as hematopoietic cells. Recently we found that it is a receptor for Pseudomonas aeruginosa and binding of bacteria was mediated through flagellin resulting in tyrosine phosphorylation of its cytoplasmic tail. We have also shown that MUC1/Muc1 is upregulated on epithelial cells during airway inflammation and its expression suppresses inflammation, thus playing an anti-inflammatory role during airway bacterial infection. Our studies on the mechanism of its anti-inflammatory action revealed that MUC1/Muc1 interacts with various Toll-like receptors (TLRs), suggesting the modulatory role of MUC1 during airway inflammation. Together with airway epithelial cells and macrophages, lung dendritic cells (LDC) are also key regulators of pulmonary inflammation in response to both inhaled pathogens and allergens. DC expresses both MUC1/Muc1 and various TLRs. However, the role of MUC1/Muc1 in DC function is not known. Interestingly, our recent preliminary studies suggest that Muc1-null mice fail to exhibit pulmonary eosinophilia and goblet cell hyperplasia as seen in wild type littermates in an ovalbumin (OVA)-induced asthma model. These results prompted us to hypothesize that the levels of Muc1 in LDC play a crucial role in the development of allergic asthma. In this R21 application, we propose to test our hypothesis with the following specific aims using a murine model of allergic asthma: In Aim 1, we determine whether mice deficient in Muc1 expression fail to develop the type-2 immune response associated with allergic asthma in response to OVA sensitization and challenge in vivo. In Aim 2, we will determine whether LDC from Muc1-null mice show any defects in number, phenotype, or function in vitro. Given the modulatory role of MUC1/Muc1 in signal transduction, it is likely that the absence of MUC1/Muc1 in DC will significantly affect their function as antigen presenting cells. If this can be proven through this exploratory/developmental grant mechanism, we plan to extend this interesting observation through an R01 application to elucidate the mechanism by which Muc1 regulates the development of asthma in response to allergens. Project Narrative: This project is based on a novel, interesting observation that mice deficient in Muc1, a protein present on the surface of airway lining cells, fails to develop asthma in a well-established mouse allergic asthma model. In this project, we will try to understand the mechanism at the cellular and molecular level. Successful completion of this project will shed valuable insights in our understanding of the development of asthma.

描述（由申请人提供）：MUC1（人类中的MUC1和非人类中的MUC1）是一种在各种癌细胞中高度表达的跨膜粘蛋白样糖蛋白，其表达也已在各种正常上皮细胞以及血肿细胞中显示。最近，我们发现它是铜绿假单胞菌的受体，通过鞭毛蛋白介导细菌的结合，导致其细胞质尾部的酪氨酸磷酸化。我们还表明，在气道炎症期间，MUC1/MUC1在上皮细胞上被上调，其表达抑制了炎症，因此在气道细菌感染过程中起着抗炎作用。我们对其抗炎作用机制的研究表明，MUC1/MUC1与各种Toll样受体（TLR）相互作用，表明MUC1在气道炎症过程中的调节作用。与气道上皮细胞和巨噬细胞一起，肺树突状细胞（LDC）也是对吸入的病原体和过敏原的响应，也是肺部炎症的关键调节剂。 DC同时表达MUC1/MUC1和各种TLR。但是，MUC1/MUC1在直流功能中的作用尚不清楚。有趣的是，我们最近的初步研究表明，如在卵巢蛋白（OVA）诱导的哮喘模型中，MUC1-NULL小鼠无法表现出肺嗜酸性粒细胞和杯状细胞增生。这些结果促使我们假设最不发达国家的MUC1水平在过敏性哮喘的发展中起着至关重要的作用。在此R21应用中，我们建议使用以下特定目的使用过敏性哮喘的鼠模型来检验我们的假设：在AIM 1中，我们确定缺乏MUC1表达的小鼠是否无法发展与OVA敏感性和体内挑战相关的2型免疫反应。在AIM 2中，我们将确定来自MUC1-NULL小鼠的LDC是否在体外表现出数量，表型或功能的任何缺陷。鉴于MUC1/MUC1在信号转导中的调节作用，DC中缺乏MUC1/MUC1可能会显着影响其作为抗原呈递细胞的功能。如果可以通过这种探索性/发展授予机制来证明这一点，我们计划通过R01应用扩展这种有趣的观察结果，以阐明MUC1调节对过敏原而调节哮喘的发育的机制。项目叙述：该项目基于一个新颖有趣的观察结果，即在气道衬里细胞表面上存在的蛋白质中缺乏小鼠在良好的小鼠过敏性哮喘模型中未能发育哮喘。在这个项目中，我们将尝试了解细胞和分子水平的机制。该项目的成功完成将为我们理解哮喘的发展提供宝贵的见解。