Macrophage Factor XIII-A in Provisional Extracellular Matrix Modification and Epithelial Repair during Acute Lung Injury - PROJECT SUMMARY Project Summary: This proposal describes a 5-year research training program that will develop Dr. Peter Moore into an independent basic and translational physician-scientist. His long-term career goal is to advance the fields of ARDS, extravascular coagulation, and epithelial repair through the elucidation of mechanisms underlying repair after acute lung injury (ALI). During this K08 Award, Dr. Moore will gain specific career development training and mentorship closely aligned with an innovative research plan. He proposes to study the role of macrophage-produced coagulation factor XIII-A in regulation of the extracellular matrix (ECM) and alveolar epithelial repair after ALI. Given its applicability to multiple pulmonary disorders and repair of injury in other organs, this work is directly relevant to the NHLBI. Candidate: Peter Moore MD, is a board-certified Pulmonary and Critical Care Medicine physician-scientist at the University of Colorado Anschutz Medical Campus. His record of academic excellence, basic science research and scientific publications demonstrates a firm commitment to a career as a clinician-scientist. Training: The proposed career development plan augments Dr. Moore's prior mentored research during his undergraduate, medical, residency, and fellowship training. He proposes to meet his short-term objectives through an integrated combination of intensive mentoring by internationally renowned experts in macrophage biology, ECM proteomics, and transglutaminase activity in tissue repair with didactic and hands-on experiences in (i) extravascular coagulation, (ii) proteomics, (iii) in vivo and ex vivo models of epithelial repair, (iv) scientific writing and presentation, and (v) laboratory leadership. Mentor / Environment: Dr. Moore has close working relationships with highly experienced mentors and collaborators who contribute expertise in macrophage and lung biology (Drs. Janssen, Schwartz, McCubbrey, Mould, Redente), ECM proteomics (Dr. Hansen), extravascular fibrin and transglutaminase activity during tissue injury/repair (Dr. Luyendyk), and innovative tissue imaging techniques (Dr. Schwartz, Redente). The proposed activities will be based at the University of Colorado and National Jewish Health, top-ranked research institutions. Research Project: The primary objective of this proposal is to identify the mechanism by which monocyte- derived macrophage (moMΦ) production of factor XIII-A (FXIII-A) enhances repair after ALI. Specifically, our studies will test the hypothesis that FXIII-A produced by moMΦ at sites of injury crosslinks components to the extracellular matrix that improves type 2 alveolar epithelial cell replication, migration, and differentiation to type 1 alveolar epithelial cells after ALI. This will be tested with well established murine models of acute lung injury and human biospecimens using specialized ECM proteomics, atomic force microscopy, and time-lapsed imaging of precision cut lung slices and decellularized lung scaffolds. In doing so, the specific contributions of moMΦ FXIII-A's modifications of the ECM to repair after acute injury will be elucidated.
