DESCRIPTION (provided by applicant): The use of gene transfer technologies and the mouse as a model of human respiratory diseases aptly summarizes the research program of the candidate, James (Jamie) Lee, Ph.D. This work forms the basis of the candidate's immediate career goals of expanding the breadth of his laboratory to include increasingly complex assessments of physiologically relevant endpoints of pathology. The achievement of these immediate goals, in turn, support the long term goals, including (i) To move the orientation of the lab from a molecular biology perspective to a physiology-based program and (ii) To expand the educational activities in mouse research within the Mayo Foundation, and Mayo Clinic Arizona in particular, and to include the regional graduate program at Arizona State University. The institutional support and commitment to research and graduate education offered by Mayo Clinic, together with the expanding local university graduate programs in biomedical research, represent unique opportunities to create a collaborative center of focused efforts using the mouse as a model system of human disease research. A critical objective of this career development plan is to recruit and train motivated students and fellows, capitalizing on the success of the laboratory's research activities. The goals of the research proposal are to define the role(s) of eosinophils and eosinophil effector functions mediating allergic inflammation and, therefore, their roles in the development of pulmonary pathologies. The proposal exploits unique eosinophil specific reagents and novel transgenic and gene knockout mice we have created in our studies of eosinophil biology. The objectives will be achieved through the completion of the following aims: (1) To determine unequivocally the contribution(s) of eosinophils to the pulmonary pathologies arising in a transgenic model of asthma generated by the co-expression of JJL-5 and eotaxin-2; (2) To define mechanisms of eosinophil effector functions responsible for the pulmonary pathologies occurring in the IL-5/eotaxin-2 transgenic model of asthma; (3) To determine if degranulation and the release of granule proteins represents a mechanism by which eosinophils contribute to the pathologies arising in the IL-5/eotaxin-2 transgenic model of asthma.