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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL084385-03
Application #
7390415
Study Section
Special Emphasis Panel (ZHL1-CSR-O (F1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2006-04-01
Project End
2011-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
3
Fiscal Year
2008
Total Cost
$126,792
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Gharib, Sina A; Johnston, Laura K; Huizar, Isham et al. (2014) MMP28 promotes macrophage polarization toward M2 cells and augments pulmonary fibrosis. J Leukoc Biol 95:9-18
Ma, Yonggang; Halade, Ganesh V; Zhang, Jianhua et al. (2013) Matrix metalloproteinase-28 deletion exacerbates cardiac dysfunction and rupture after myocardial infarction in mice by inhibiting M2 macrophage activation. Circ Res 112:675-88
Ma, Yonggang; Chiao, Ying Ann; Zhang, Jianhua et al. (2012) Matrix metalloproteinase-28 deletion amplifies inflammatory and extracellular matrix responses to cardiac aging. Microsc Microanal 18:81-90
Johnston, Laura K; Rims, Cliff R; Gill, Sean E et al. (2012) Pulmonary macrophage subpopulations in the induction and resolution of acute lung injury. Am J Respir Cell Mol Biol 47:417-26
Manicone, Anne M; Harju-Baker, Susanna; Johnston, Laura K et al. (2011) Epilysin (matrix metalloproteinase-28) contributes to airway epithelial cell survival. Respir Res 12:144
Manicone, Anne M; Birkland, Timothy P; Lin, Michelle et al. (2009) Epilysin (MMP-28) restrains early macrophage recruitment in Pseudomonas aeruginosa pneumonia. J Immunol 182:3866-76
Manicone, Anne M (2009) Role of the pulmonary epithelium and inflammatory signals in acute lung injury. Expert Rev Clin Immunol 5:63-75
Manicone, Anne M; McGuire, John K (2008) Matrix metalloproteinases as modulators of inflammation. Semin Cell Dev Biol 19:34-41