This proposal describes a 2-year research fellowship program, which will allow the principal investigator to begin to develop an academic career in Pulmonary Medicine. The principal investigator has completed a thorough residency training program in Internal Medicine and is currently training as a fellow in Pulmonary Diseases and Critical Care Medicine. The proposed research will investigate the metabolic programming of macrophage subsets in the setting of lung repair, which should prove to be applicable in a host of lung conditions. Dr. William Janssen, an expert in macrophage biology, will be one of two co-mentors to the principal investigator during her scientific development in the field of lung repair Dr. Janssen is an exemplary faculty member in the Pulmonary and Critical Care Medicine Division at National Jewish Health and the University of Colorado. Also serving as a co- mentor will be Dr. Peter Henson, an expert in the field of lung injury and repair at National Jewish and the University of Colorado. He has an outstanding record of mentoring fellows into independent investigators. The overall research goal of this proposal is to determine the role of metabolism in driving reparative programming of macrophages following lung inflammation. We hypothesize that increased levels of glycolysis are necessary for orchestration of lung repair, through the production of the pro-repair molecules and possibly, direct cell-cell interactions. We will characterize the specific metabolic changes that occur during lung repair and measure metabolite profiles in order to elucidate the pathways responsible for these changes. We will also measure changes in the pro-repair molecule production in resident and recruited alveolar macrophages to identify the roles of macrophage subsets during repair. Our experiments will use the lipopolysaccharide mouse model of acute lung injury. We will use an in vitro scratch wound assay to assess the functional significance of reparative programming on alveolar epithelial repair. Determining how metabolic programming differentially influences the phenotypes of macrophage subsets will provide novel insight into lung biology and repair following lung injury. This may be applicable to a variety of lung conditions and may provide opportunities for new therapeutic interventions for the acute respiratory distress syndrome. It wil also provide a basis for future work as the principal investigator moves from fellowship, to junior investigator, to independent researcher.
The ability of the lung to repair itself following injury is of crucial importance for recovery from several pulmonary diseases. We are studying the mechanisms by which immune cells, specifically alveolar macrophages, coordinate lung repair and how metabolic programming influences their reparative phenotypes. Specifically, we are studying two types of macrophages, resident macrophages and recruited bone marrow derived cells, and testing the importance of glycolysis in driving their ability to promote alveolar epitheial cell repair.
|McCubbrey, Alexandra L; Barthel, Lea; Mohning, Michael P et al. (2018) Deletion of c-FLIP from CD11bhi Macrophages Prevents Development of Bleomycin-induced Lung Fibrosis. Am J Respir Cell Mol Biol 58:66-78|
|Mould, Kara J; Barthel, Lea; Mohning, Michael P et al. (2017) Cell Origin Dictates Programming of Resident versus Recruited Macrophages during Acute Lung Injury. Am J Respir Cell Mol Biol 57:294-306|