This research program deals with a protein that we have identified through its IgE-binding activity and extensively studied. This protein is now known as galectin-3, a member of a large family of beta-galactoside-binding animal lectins. We have accumulated a great deal of information on various aspects of galectin-3 which has allowed us to hypothesize that galectin-3 is a broad-spectrum amplifier of inflammatory response. We propose to continue to study the role of galectin-3 in inflammation by focusing on the following three specific aims. 1. Establishment of the function of galectin-3 inflammatory cells. We have shown various activities of galectin-3 by using exogenously added protein. THe role of galectin-3 in inflammation will be more firmly established by demonstrating that the endogenous lectin can participate in these activities. CO-culture systems in which galectin-3 secreted from macrophages and epithelial cells activates mast cells will be studied as examples. We will first establish conditions in which galectin-3 is released by inflammatory cells. The activity of galectin-3 i potentialteing the activation of inflammatory cells induced by other stimuli will also be investigated. Cells from galectin-3 mice will be used extensively for these analyses. 2. Development of animal models for establishing the role of galectin-3 inflammation. MOuse models of airway inflammation and cutaneous inflammation will be used to analyze the expression and secretion of galectin-3 in inflamatory responses. Galectin-3-deficient mice will be used to evaluate the role of galaectin-3 in airway and cutaneous inflammation. 3. Elucidation of the molecular basis for galectinn-3's activation of inflammatory cells. The realtionship between galectin-3's activation of mast cells and its recognition of Fc (epsilon) RI will be investigated. Molecular requirements for galectin-3's abilty to activates leukocytes will be delineated by focusing on galectin-3's self association property. Covalent galectin-3 dimers will be generated and compared with the mononomeric protein for various activities. AMino acid sequence in the amino-terminal region that is responsible for galectin-3's self association will be identified.
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