ROLE OF MUC1 IN THE GENESIS OF ALLERGIC ASTHMA

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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.