Natural killer cells in pulmonary ischemia-reperfusion injury

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This is an application for a BLRD CDA-2 award for Dr. Daniel Calabrese, a staff physician at the SFVA and an Assistant Professor in the Division of Pulmonary and Critical Care at the University of California, San Francisco who is establishing himself as an investigator in clinical research into the immunology of acute lung injury. This CDA-2 award will provide Dr. Calabrese with the necessary support to accomplish the following goals: (1) to improve the understanding of natural killer cells, their receptors, and their ligands in ischemia-reperfusion injury (2) to acquire theoretical and practical skills in mouse and human immunology and bioinformatics (3) to establish mechanistic foundations for future interventional trials to improve lung injury syndromes and (4) to establish an independent basic laboratory scientist career focused on innate immunology in lung disease. To achieve these goals, Dr. Calabrese has assembled a mentoring team consisting of his primary mentor, Dr. John Greenland, an international expert in pulmonary immunology and lung injury, and a senior co-mentor Dr. Mary Nakamura, an expert in the innate immune response to thoracic ischemia-reperfusion injury (IRI). He has assembled a career development committee and scientific advisory board that will additionally consist of: Dr. Lewis Lanier, an expert in natural killer (NK) cell biology with over 50 mentees and 250 publications; Dr. Mark Looney, an expert in innate mechanisms of acute lung injury and mouse models of lung transplantation; and, Dr. Jonathan Singer, director of the UCSF lung transplant research program and an expert in lung transplant epidemiology research. Additionally, he will have tutorials and scientific advice from Drs. Jason Christie, Dara Torgerson, Matthew Spitzer, Michael Matthay, Anatoly Urisman in multi-institutional collaboration, statistical genetics, mass cytometry, human lung experimental models, and pathology, respectively. The proposed research will expand on strong preliminary data in two mouse models of lung injury and human samples showing a paradigm- shifting role for NK cells in ischemia-reperfusion injury (IRI). The proposed study will test the hypothesis that NK cells directly mediate the lung injury observed in experimental and human ischemia-reperfusion injury through receptor-specific interactions in the following specific aims: (1) To determine how NK cells are activated and induce mouse pulmonary IRI (2) To determine how NK cells traffic to the lung during mouse pulmonary IRI (3) To evaluate NK cell activation in human IRI. This work is innovative as these studies will make use of advanced mouse surgical models and cutting-edge technologies such as next generation flow cytometry and multiplex protein quantification to define a key innate immune response following lung injury. This research is significant for veterans as it will identify pre-clinical and clinical therapies to use in veteran-health specific diseases of acute respiratory distress syndrome, advanced lung disease, myocardial infarction, and stroke. This work is novel as it will define a new role of NK cell receptors and stress ligands in IRI.