ROLE OF MUC1 IN THE GENESIS OF ALLERGIC ASTHMA

描述（由申请人提供）：MUC 1（人中的MUC 1和非人中的Muc 1）是在各种癌细胞中高度表达的跨膜粘蛋白样糖蛋白，并且其表达也已在各种正常上皮细胞以及造血细胞中显示。最近我们发现它是铜绿假单胞菌的一种受体，并且通过鞭毛蛋白介导细菌的结合，导致其胞质尾区的酪氨酸磷酸化。我们还发现，MUC 1/Muc 1在气道炎症过程中在上皮细胞上上调，其表达抑制炎症，从而在气道细菌感染过程中发挥抗炎作用。我们对其抗炎作用机制的研究表明，MUC 1/Muc 1与多种Toll样受体（TLRs）相互作用，提示MUC 1在气道炎症中的调节作用。与气道上皮细胞和巨噬细胞一起，肺树突状细胞（LDC）也是响应吸入病原体和过敏原的肺部炎症的关键调节因子。DC表达MUC 1/Muc 1和各种TLR。然而，MUC 1/Muc 1在DC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，Muc 1基因敲除小鼠在卵清蛋白（OVA）诱导的哮喘模型中没有表现出与野生型同窝小鼠相同的肺嗜酸性粒细胞增多和杯状细胞增生。这些结果提示我们推测LDC中Muc 1的水平在过敏性哮喘的发展中起着至关重要的作用。在这个R21应用中，我们提出使用过敏性哮喘的小鼠模型来测试我们的假设，具有以下特定目的：在目的1中，我们确定Muc 1表达缺陷的小鼠是否不能在响应于OVA致敏和体内激发时发展与过敏性哮喘相关的2型免疫应答。在目标2中，我们将确定来自Muc 1-null小鼠的LDC是否在体外显示任何数量、表型或功能缺陷。鉴于MUC 1/Muc 1在信号转导中的调节作用，DC中MUC 1/Muc 1的缺失可能会显著影响其作为抗原呈递细胞的功能。如果这可以通过这种探索性/发展性资助机制得到证明，我们计划通过R 01应用程序扩展这一有趣的观察结果，以阐明Muc 1调节哮喘发生的机制。项目叙述：该项目是基于一个新的，有趣的观察，小鼠缺乏Muc 1，一种存在于气道衬里细胞表面的蛋白质，未能在一个完善的小鼠过敏性哮喘模型中发展哮喘。在这个项目中，我们将尝试在细胞和分子水平上了解其机制。成功完成这个项目将为我们了解哮喘的发展提供有价值的见解。

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.