This proposal describes a five-year training program that will ultimately develop Dr. Kara Mould into an independent academic basic science investigator. Her long-term career goal is to advance the field of macrophage biology through the elucidation of targets for lung repair and the treatment of patients with the acute respiratory distress syndrome or inflammatory lung diseases. During this K08 Award, Dr. Mould will gain specific career development training and mentorship closely aligned with an innovative research plan. She proposes to study the affect of arginine metabolism on alveolar macrophage programming in models of acute lung injury. Given its applicability to multiple pulmonary disorders and potential applicability to repair of injury in other organs, this work is directly relevant to the NHLBI. Candidate: Dr. Mould is a board-certified Pulmonary and Critical Care Medicine physician at the University of Colorado School of Medicine. She is in the final year of fellowship training, having elected to complete an optional year of dedicated research. Her previous record of academic excellence, basic science research, and scientific publications demonstrates a firm commitment to a career as an academic clinician-scientist. Training: The proposed career development plan augments Dr. Mould's prior mentored research during her undergraduate, medical, residency, and fellowship training. She proposes to meet her short-term objectives through an integrated combination of intensive mentoring by internationally renowned experts in macrophage biology and didactic and hands-on experiences in (i) Immunology, (ii) metabolic programming of immune cells (iii) bioinformatics, (iv) scientific writing and presentation, and (v) laboratory leadership. Mentors/Environment: Dr. Mould has established close working relationships with highly experienced mentors and collaborators who contribute expertise in macrophage and lung biology (Drs. Henson and Janssen), metabolomics (Dr. D'Alessandro), bioinformatics (Dr. Fingerlin), human lung and epithelial biology (Dr. Mason), endothelial biology (Dr. Petrache), and career development of clinician-scientists (Drs. Douglas, Eickelberg, and Voelker.) The proposed activities will be based at National Jewish Health with support from the University of Colorado, both renowned respiratory medical centers and world-class research institutions. Research Project: The primary objective of this proposal is to identify the mechanism by which alveolar macrophages are programmed to resolve inflammation and promote repair of the injured lung. Specifically, our study will test the hypothesis that the metabolic enzyme, arginase 1, is a critical checkpoint for both inflammatory and reparative programming of alveolar macrophages. This will be tested using a well- established murine model of lung injury and primary cells isolated from diseased human lungs or non-diseased controls. In doing so, the specific contribution of arginine metabolism to macrophage programming and pathways that regulate recovery from inflammatory lung diseases will be elucidated.
Inflammatory lung diseases, including the acute respiratory distress syndrome (ARDS), affect over 1 million individuals in the United States annually. We believe that lung immune cells, alveolar macrophages, are responsible for promoting repair of the injured lung and will test whether metabolism of an amino acid, arginine, through specific pathways is an important checkpoint in limiting inflammation and promoting repair. In doing so, this proposal will help identify mechanisms that underlie the resolution of inflammatory lung diseases and lay the groundwork for development of novel treatments for these conditions.