ROLE OF MUC1 IN THE GENESIS OF ALLERGIC ASTHMA

描述（由申请人提供）：MUC1（人MUC1，非人MUC1）是一种在多种癌细胞中高度表达的跨膜黏液样糖蛋白，在多种正常上皮细胞和造血细胞中也有表达。最近我们发现它是铜绿假单胞菌的受体，细菌的结合是通过鞭毛蛋白介导的，导致其细胞质尾部酪氨酸磷酸化。我们还发现，在气道炎症过程中，MUC1/ MUC1在上皮细胞上表达上调，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发现，MUC1/ MUC1与多种toll样受体（TLRs）相互作用，提示MUC1在气道炎症中的调节作用。肺树突状细胞（LDC）与气道上皮细胞和巨噬细胞一起，也是肺部炎症对吸入病原体和过敏原反应的关键调节因子。DC既表达MUC1/ MUC1，也表达多种tlr。然而，MUC1/ MUC1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，在卵清蛋白（OVA）诱导的哮喘模型中，muc1缺失的小鼠没有表现出肺嗜酸性粒细胞增多和杯状细胞增生，这在野生型幼崽中是可见的。这些结果促使我们假设ldl中Muc1的水平在过敏性哮喘的发展中起着至关重要的作用。在这项R21应用中，我们提出使用过敏性哮喘小鼠模型来验证我们的假设，其具体目的如下：在Aim 1中，我们确定Muc1表达不足的小鼠在体内对OVA致敏和攻击是否不能产生与过敏性哮喘相关的2型免疫反应。在Aim 2中，我们将确定muc1缺失小鼠的LDC在体外是否在数量、表型或功能上存在缺陷。考虑到MUC1/ MUC1在信号转导中的调节作用，DC中MUC1/ MUC1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/发育性资助机制得到证明，我们计划通过R01申请来扩展这一有趣的观察，以阐明Muc1调节过敏原反应中哮喘发展的机制。项目描述：该项目基于一项新颖有趣的观察，即在一种成熟的小鼠过敏性哮喘模型中，缺乏Muc1（一种存在于气道内衬细胞表面的蛋白质）的小鼠不能发展为哮喘。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。这个项目的成功完成将为我们理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.