Epilysin in Lung Immunity

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This proposal outlines a 5-year training program for the development of a physician-scientist in the field of Pulmonary Medicine. The objective of the proposed training plan is to provide the skills necessary to use modern biological tools to address basic questions related pulmonary disease and inflammation. This program includes formal didactics, participation in journal clubs, presentation at local and national meetings and manuscript preparation and publication. The principal investigator will be mentored by Dr. William Parks, who not only has extensive experience mentoring successfully-funded independent investigators, but also is a leader in his field of matrix metalloproteinase (MMP) biology, tissue injury and repair. The scientific program will focus on identifying the role and substrate of a newly identified MMP, epilysin, in lung injury and inflammation. Preliminary studies in epilysin-null mice reveal an increase in early macrophage recruitment to the lung during infection and indicate that epilysin serves as a negative regulator for macrophage influx. The first aim of this proposal is to characterize the inflammatory phenotype in epilysin-null mice. We will test our hypothesis that epilysin is a key effector of macrophage influx, by assessing several models of injury/inflammation in the lung and peritoneum. Our second aim will determine the cellular source of epilysin that regulates macrophage recruitment into the lungs. By generating chimeric mice via bone marrow transplantation, we will test our hypothesis that macrophage-derived epilysin controls macrophage influx. Our third aim will determine the mechanism by which epilysin mediates macrophage recruitment. We plan to use animal and cell models to determine epilysin's substrate(s), which we hypothesize is a macrophage cell surface protein, such as a chemokine receptor or adhesive protein. These studies will advance our understanding of how macrophage influx is regulated and restrained, thereby identifying an intrinsic mechanism that limits over-exuberant inflammation. The knowledge gained from this research will have important implications in understanding and treating inflammatory diseases. This application takes advantage of the resources and mentoring available at the University of Washington to provide the investigator with the tools necessary to become a successful independent investigator in the field of Pulmonary Medicine.