Research Project
7148233
[unreadable] DESCRIPTION (provided by applicant): Allergic inflammation is a complex disease that involves the trafficking and mobilization of multiple leukocytes, including eosinophils and T-cells, to sites of inflammation. Increased expression of Th2 cytokines, chemokines, vascular adhesion molecules and growth factors leading to exacerbation of the inflammatory response, including increased airway hyperactivity (AHR), airway remodeling and pulmonary angiogenesis are observed during airway allergic inflammation. Since eosinophils play an important role in the pathogenesis of allergic inflammation, in the last decade we have focused our attention on the mechanisms by which this cell type is generated, how it interacts with the vascular endothelium and how it is recruited to sites of inflammation. These studies have resulted in the identification of key molecules involved in the sequestration of eosinophils to different vascular beds such as the peritoneum and the pulmonary vascular bed. Our preliminary studies suggest that in addition to cell surface selectins and integrins, galectin- 3 (Gal-3), a carbohydrate-binding lectin that recognizes N-glycans expressed by MgatS, can (i) function as a novel vascular and cell adhesion molecule to support eosinophil trafficking, (ii) participate in the generation of Th2 cytokines and (iii) induce AHR in mice. In this competing continuation, we hypothesize that Gal-3 as well as N-glycans expressed by MgatS play an important role in the pathogenesis of acute and chronic airway allergic inflammation including asthma. To examine this, we have proposed three specific aims. In the first aim, using intravital microscopy, we will examine the function of Gal-3 as a novel adhesion molecule that supports cell adhesion by binding to multiple ligands, including N-glycans containing poly N- acetyllactosamine residues, VCAM-1 and alpha4 integrins, to support trafficking of eosinophils under conditions of flow in different vascular beds. In the next aim, using Gal-3-/- and Mgat-5-/- mice, we will determine the role of Gal-3 and Mgat5 in mediating immune responses including, AHR, expression of adhesion molecules and chemokines, Th1/Th2 cytokine release, mast cell activation and survival of inflammatory leukocytes during chronic allergic inflammation. Finally, based on our observation that Gal-3 is expressed in the airways and lung tissue associated with airway remodeling in chronically allergen-challenged mice, we propose to examine the mechanisms by which Gal-3 and its N-glycan-containing ligands expressed by MgatS promote airway remodeling and pulmonary angiogenesis associated with allergic inflammation utilizing Gal-3-/- and Mgat-5-/- mice. Overall, the proposed studies will delineate the importance of Gal-3 and its ligands in acute and chronic phases of airway allergic inflammation. Understanding the role of lectin-carbohydrate interactions in allergic inflammation has the potential to lead to the development of glycan-based therapies (or their mimetics) for the treatment of allergic diseases. [unreadable] [unreadable] [unreadable]
