Investigations of the basic mechanisms of lung damage by eosinophil involvement in pulmonary diseases will be the means of achieving the major goal of the Physician Scientist Award which is the development of a solid foundation in research techniques related to cellular physiology and biochemistry that will enable a physician to develop a career as an independent researcher. The mechanisms of tissue damage caused by the eosinophil in lung diseases will be studied under the guidance of Peter Weller, M.D., Department of Medicine, Harvard Medical School, Beth Israel Hospital and Elizabeth Simons, Ph.D., Department of Biochemistry, Boston University School of Medicine, cosponsors of this application. Phase I will be an educational phase to include didactic and laboratory training designed to instruct the applicant in principles of biochemistry and cell physiology. The background and technique of protein purification and characterization will be learned by continuing work in Dr. Weller's laboratory involving lymphokines that specifically stimulate chemotaxis and other responses in human eosinophils. Under the tutelage of Dr. Simons, the laboratory learning phase will also include the understanding and application of fluorescent probe techniques to investigate transmembrane potential, cytoplasmic calcium flux and intracellular pH changes during leukocyte activation. These techniques will then be applied in Phase II to study eosinophil activation by determining the functional characteristics of information transduction from initiation of activation by a stimulus to cellular response. This will be done by comparing eosinophil responses to different stimuli including lymphokines, which may result in chemotaxis, oxidative burst or degranulation, and also by determining the acquisition of these response capabilities during eosinophil differentiation. By studying eosinophils from normal hosts and those with pulmonary diseases, these investigations will provide knowledge about the mechanisms of eosinophil recruitment and activation, and will provide insights into the means whereby eosinophils may contribute to tissue damage in pulmonary diseases.
