PROJECT SUMMARY / ABSTRACT This proposal describes a 2-year research fellowship program, which will allow the principal investigator to develop an academic career in Pulmonary Medicine. The principal investigator has completed residency training in Internal Medicine and is currently training as a fellow in Pulmonary Diseases and Critical Care Medicine. The proposed research will investigate the origin, location, and signal receptors responsible for interstitial macrophage expansion during acute lung inflammation from direct epithelial and indirect systemic stimuli in mice. The principal investigator will have a two-tiered mentorship team within the same laboratory. William Janssen MD, an expert in macrophage biology and exemplary physician-scientist at National Jewish Health and the University of Colorado, is the primary mentor and sponsor and will provide project oversight and career mentorship. Dr. Alexandra McCubbrey PhD, a junior faculty lung immunologist, will serve as the co-sponsor and will provide hands-on training in laboratory techniques and data analysis. The overall research goal of this proposal is to determine differences in interstitial macrophage responses to acute inflammation from direct and indirect stimuli. We hypothesize that interstitial macrophage expansion during acute inflammation is driven by recruitment of circulating monocyte-derived macrophages rather than proliferation of resident macrophages. Further, direct lung inflammation results in macrophage recruitment to multiple sites within the lung parenchyma while indirect inflammation results in macrophage recruitment primarily to the alveolar septa. Differences in chemokine receptors will target macrophage recruitment to the interstitium versus airspace. Flow cytometry and immunofluorescence will quantify and localize recruited macrophages in an established transgenic reporter mouse model that allows lineage tracing of interstitial macrophages. Mixed bone marrow chimera mice and chemokine receptor knockout mice will be used to evaluate contribution of specific chemokine receptors to inflammatory macrophage migration. Determining the interstitial macrophage response to different inflammatory stimuli will provide novel insights into variations in lung inflammation. Findings from these experiments have potential implications for human lung disease like the acute respiratory distress syndrome. Further, as interstitial pulmonary macrophages are located adjacent to many structures with important biologic structures these findings may have applications to many lung disorders. This work will also serve as the basis for future work as the principal investigator moves from fellowship, to junior investigator, to independent researcher.

F32HL156289

2021-07-01

2022-06-30