PROJECT SUMMARY/ABSTRACT Neutrophils play an important role in the pathogenesis of several common lung diseases including pneumonia, asthma, and chronic obstructive pulmonary disease. Yet, no neutrophil-specific therapies are available to treat these conditions. A deeper understanding of the mechanisms that control neutrophilic lung inflammation may enable development of such therapies. Our group investigates chitinase 3-Like-1 (Chi3L1), a secreted immune protein with cytokine-like properties. In preliminary studies using a murine pneumonia model, we have found that Chi3L1 regulates neutrophil cell fate. Specifically, we have shown that Chi3L1 suppresses apoptosis, promotes formation of neutrophil extracellular traps (i.e. NETosis, a pro-inflammatory form of cell death), and worsens lung injury. In this proposal, we seek to build upon these preliminary findings through four sub-aims. First, we will identify the receptor on neutrophils that mediates the pro-NETotic/anti-apoptotic effect of Chi3L1. Second, we will elucidate the intracellular signaling pathways responsible for this effect. Third, we will assess the pathogenicity of Chi3L1 in a murine model of neutrophilic asthma. Fourth, we will use sputum from patients with neutrophilic asthma to establish the relevance of Chi3L1 in human disease. Successful completion of these aims will provide important insight into the pathogenesis of neutrophilic lung diseases and help to identify new therapeutic strategies for these conditions. This research will also provide a rigorous training program to prepare the applicant for an independent career as a physician-scientist studying neutrophil biology in the lung. Career Development. To support achievement of these research and career goals, we have assembled a world-class team of mentors with expertise in each proposed area of investigation including pneumonia, asthma, neutrophil signaling, NETosis, and translational biology. A tailored curriculum of relevant coursework, intramural meetings, and national conferences has been developed to reinforce the training gained through mentored research. Environment. Yale School of Medicine represents an ideal setting for this work given its collaborative atmosphere, cutting-edge technological facilities, and abundance of internationally-renowned investigators. The Section of Pulmonary, Critical Care and Sleep Medicine (wherein the proposed research will take place) is deeply committed to the success of early career physician-scientists like the candidate, as evidenced by its seven current K awardees. The Department of Internal Medicine is similarly committed, as they have guaranteed 75% protected research time for the duration of this award. Finally, the candidate is well- prepared to execute the proposed aims, having received fourteen years of training in biomedical science through Medical-Scientist and Physician-Scientist Training Programs (MSTP and PSTP).