The long-term objective of this application is to establish the basis for novel approaches to the treatment of asthma. Asthma affects at least 17 million Americans and has a large direct and indirect societal impact. Despite intensive investigation the mechanisms that are required for expression of the asthma phenotype are not well understood. Developing new therapeutic or preventive strategies depends on better understanding the factors that are required for allergen to alter airway responses and cause asthma symptoms. To date, the major focus of these efforts has been on protein-protein interactions. There is increasing evidence that protein-carbohydrate interactions are involved in transducing biological signals and that lectins, including the b-galactoside binding S-type lectin galectin-3, have effects on the cells and molecular mediators of the allergic response. Our objectives are to understand why galectin-3 is required for expression of the asthma-like phenotype. Our first 2 aims use established mouse models to investigate the galectin-3 mechanisms that are required for the expression of asthma. Galectin-3 interacts with its ligand 90K protein in a manner that may be relevant to the expression of asthma. In specific aim 3 we will study the interaction of galectin-3 with its counter-ligand the mouse homologue of human 90K protein (MAMA). We will study their interaction in cells and intact mice and compare the phenotype of galectin-3 and MAMA protein +/+ and -/- mice. These studies will provide the mechanistic understanding that will allow manipulation of these pathways for benefit in asthma. Specific aims: 1. To elucidate the mechanisms by which allergen-induced airway hyperresponsiveness is dependent on galectin-3. 2. To elucidate the galectin-3-dependent mechanisms that are required for allergen-induced recruitment of eosinophils and neutrophils to the airways. 3. To define the interaction of galectin-3 with the murine homologue of 90K protein for expression of the asthma-like phenotype. These studies will provide new insights into the complex role of lectins and their ligands in allergic diseases.