Interstitial macrophages in cigarette smoke-induced small airway remodeling

PROJECT SUMMARY Project Summary: This proposal describes a 5-year research training program that will develop Dr. Patrick Hume into an independent basic and translational physician-scientist investigator. His long-term career goal is to advance the fields of COPD and macrophage biology through the elucidation targets to block or repair the development of small-airways disease in cigarette smokers. During this K08 Award, Dr. Hume will gain specific career development training and mentorship closely aligned with an innovative research plan. He proposes to study the role of Lyve-1 positive interstitial macrophages in the development of small airway pathology induced by chronic cigarette smoke. Given the broad applicability to COPD, this work is directly relevant to the NHLBI. Candidate: Patrick Human MD, PhD is a board-certified Pulmonary and Critical Care Medicine physician- scientist at National Jewish Health in Denver, CO. His record of basic science research, Ph.D. training and scientific publications demonstrates a firm commitment to a career as an academic clinician-scientist. Training: The proposed career development plan augments Dr. Hume’s prior mentored research during his undergraduate, doctoral, medical residency and fellowship training. He proposes to meet his short-term objectives through an integrated combination of intensive mentoring by internationally renowned experts in macrophage biology and COPD pathogenesis with didactic and hands-on experiences in (i) data analysis, (ii) cell biology, (iii) hyaluronic acid signaling, (iv) scientific writing and presentation, and (v) laboratory leadership. Mentor / Environment: Dr. Hume has close working relationships with highly experienced mentors and collaborators who contribute expertise in macrophage and lung biology (Drs. Janssen and Petrache), COPD pathogenesis and hyaluronic acid signaling (Dr. Petrache), matrix metalloproteinase biology and tissue remodeling (Dr. Redente), creation of transgenic mouse models (Dr. Matsuda) and design-based stereology (Dr. Smith). The proposed activities will be based at National Jewish Health, a top-ranked research institution. Research Project: The primary objective of this proposal is to identify the mechanism by which peribronchial interstitial macrophages (PBIMs) mediate airway wall remodeling and pathogenesis in response to chronic cigarette smoke exposure. Specifically, our studies will test the hypothesis that Lyve-1 expressed on a subset of PBIMs binds to hyaluronic acid resulting in matrix metalloproteinase 9 (MMP-9) production, leading to airway wall remodeling and fibrosis. This will be tested in human and murine lung tissue using quantitative morphometry and immunofluorescence, flow cytometry, in vitro models of hyaluronic acid signaling, and transgenic animal models. In doing so, the specific relationships between Lyve-1+ PBIM recruitment, MMP-9 production, and airway wall remodeling will be elucidated.