This application, which comprises five projects and three cores, is designed to identify and characterize in detail genetic and cellular factors that can contribute significantly to the development, expression and/or severity of asthma. The clinical projects (Project 1) will take advantage of Stanford?s Human Genome Center, and its new SNP facility, to identify genes that importantly contribute to the development and/or expression of asthma and allergy. Candidate genes to be investigated will be selected based on both existing evidence about the genetics of asthma and the findings in the other four projects. Each of these other four projects will be based, in whole or in part, on the use of animal models of asthma to test definitively, in vivo, specific hypotheses about how individual cells (e.g., mast cells, in Project 2) or their products (e.g., the newly identified micosal epithelial chemokine, CCL28 in Project 3 phosphodiesterase 4 isoenzymes in Project 4, or prostanoids and their receptors in Project 5 can influence the expression of key characteristics of asthma, such as the development of allergic inflammation and tissue remodeling, and the development and persistence of airway hyperreactivity (AHR). Moreover, by using mutant mouse strains that have been develo9ped by transgenic and gene-targeting approaches, we will be able to examine directly the roles of specific genes (or genetic alterations), including some of those to be analyzed in our clinical project, on the expression of certain key phenotypic characteristics of asthma in vivo.
