Galectin-3 is a member of a protein family defined by affinity for beta-galactoside-containing sugars and consensus sequences. Previous in vitro studies have suggested a role for galectin-3 in promotion of inflammatory responses and recent studies with galectin-3-deficient (gal3-/-) mice lend strong support to this. Gal3-/- mice exhibit significantly reduced allergic airway inflammation; gal3-/- mice mount significantly lower IgE responses to systemic immunization; bone marrow-derived mast cells (BMMC) from gal3-/- mice degranulate less effectively when activated in vitro; gal3-/- BMMC contain a significantly lower amount of c-Jun N-terminal kinase (JNK) compared with gal3+/+ cells. We have also obtained data suggesting that galectin-3 activates NF-kB. Galectin-9 is another member of the galectin family recently shown to be a potent eosinophil chemoattractant. We propose to continue to study the roles of these galectins in allergic inflammation. 1. Elucidation of the mechanisms of galectin-3's promotion of airway inflammation. We will determine whether galectin-3 exerts its influence on the allergic airway inflammation through upregulation of IgE; determine whether galectin-3 plays a role in T cell differentiation to Th2 cells; and determine the role of galectin-3 expressed in mast cells in regulation of airway inflammation. 2. Elucidation of the mechanisms of galectin-3's regulation of mast cell activation. The role of galectin-3 in mast cell-mediated responses in vivo will be studied. The mechanisms by which galectin-3 regulates mast cell activation will be elucidated, focusing on the interactions between galectin-3 and JNK as well as other proteins that contain Src homology 3 (SH3) domains. The role of galectin-3 in regulation the NF-kB response will be investigated. 3. Investigation of galectin-9's eosinophil chemoattractant activity. The role of galectin-9 in allergic inflammation will be established by confirming the expression of galectin-9 under inflammatory conditions. The contribution of galectin-9, relative to other chemokines, in attracting eosinophils in murine models will be determined. The galectin-9 receptor will be identified. The long-term goals are to understand the molecular and cellular mechanisms of allergic inflammation and to develop new strategies for treating allergic diseases by using inhibitors of galectin-3 and galectin-9.
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