The goal of this project is to provide a well-supervised, structured training program that will allow the candidate to pursue her interest in pulmonary immunology and develop the skills and experience needed to develop into an independent academic physician-scientist. This will be accomplished by participation in a carefully organized training program and by the completion of a focused research project. An important feature of this program will be co-sponsorship by a Ph.D. immunologist (Dr. Ellen Pure) at the Wistar Institute and by a Physician-Scientist (Dr. Steven Albelda) in the Pulmonary Division at the University of Pennsylvania. 1. Training Plan: During the first three years of the proposal, the candidate will work primarily at laboratories at the Wistar Institute. She will enroll in immunology and molecular biology graduate courses at the University of Pennsylvania. This will be supplemented by active participation in laboratory meetings and journal clubs, and by attendance at seminars sponsored by the Wistar Institute, the Pulmonary Division and the Immunology graduate group. Frequent meetings with the sponsors and an advisory committee will be held. Progress will be monitored by research productivity as well as by evidence of mastery of concepts and ideas. In the last two years of the project, the candidate will return to the Pulmonary Division to establish her own laboratory, while continuing to maintain close contacts with the sponsors and advisory committee. 2. Research Plan: The focus of the research plan will be to expand on preliminary studies showing that interactions of mitogen-activated T lymphocytes with airway smooth muscle (ASM) via integrins and CD44 may be an important component of the inflammatory response in asthma. The central hypothesis of the proposal is that the ASM cell plays an important role in the inflammatory response that characterizes asthma. Using a model of human peripheral blood T cells and human ASM in culture, three specific aims are proposed: 1) to define and characterize the specific cell surface receptors that mediate adhesion between allergen-reactive T cells and ASM, 2) to determine the mechanisms used by inflammatory mediators in regulating adhesion molecule expression and T cell adhesion to ASM, with special focus on cAMP-dependent kinase pathways, and 3) to define the effect of T cell adhesion on specific ASM functions including proliferation, cytokine production adhesion receptor and MHC class II expression. Completion of this project will allow the candidate to receive the training necessary to compete for future NIH funding and will provide important new information about the role of lymphocyte-ASM interactions in asthma.
