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 and Critical Care Medicine. The proposed research will investigate the role of extracellular ribonucleic acids in the setting of inflammation in the lungs, which should prove to be applicable in a host of inflammatory lung conditions. Dr. William Janssen, an expert in macrophage biology will be one of two co-mentors to the principal investigator during in his scientific development in the field o lung inflammation. Dr. Janssen is a well-respected faculty member in the Pulmonary Critical Care Medicine Division at National Jewish Health in Denver, as well as at the University of Colorado Denver. Also serving as Co-Mentor will be Dr. Peter Henson, an expert in the field of lung injury and repair at National Jewish and UC Denver. Dr. Henson has been extremely successful in mentoring fellows into independent investigators. Our overall research goal is to determine the role of extracellular ribonucleic acids (RNA) in the promotion of lung inflammation. We hypothesize that this extracellular RNA, released from necrotic and apoptotic cells in the setting of lung injury serve as a mechanism by which inflammation is amplified. We will characterize the RNA, which is present in the alveoli of injured and inflamed lungs, and elucidate the mechanism by which it exerts its pro-inflammatory effect. The sensing of RNA by cells has been studied most extensively in the setting of viral infection. From those studies, we know that TLRs 3, 7, and 8 as well as the various RIG-I like receptors (RLR) can produce pro-inflammatory signaling in response to RNA. Our experiments will use mouse models of acute lung injury, both LPS and acid induced, to study RNA's pro- inflammatory properties. We will use sensor deficient mouse strains to study the function of TLR3, TLR7 and mitochondrial antiviral signaling protein (MAVS), which is the common RLR adaptor protein, in our lung injury models. We will also investigate whether the enzymatic degradation of the extracellular RNA will attenuate the inflammatory response. Determining how extracellular RNA can amplify the inflammatory response will provide novel insight into lung biology in inflammation and injury. This may be applicable to a variety of inflammatory lung conditions, and possibly demonstrate opportunities for new therapeutic interventions in the future. It will also provide a basis for futre work as the principal investigator moves from fellowship, to junior investigator, to independent researcher.
While inflammation plays a crucial role in the lung's host defense mechanism, uncontrolled inflammation, as seen in several disease states in the lungs, can have devastating effects. We are studying mechanisms by which the inflammation is promoted in the lungs of mice using models of acute lung injury, a condition driven by excessive inflammation. Specifically, we are studying how ribonucleic acids released from injured and dying cells amplify inflammation in the lungs.
| 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 |
