AND ABSTRACT This is an application for a K08 award for Dr. Daniel Calabrese, an Assistant Professor in the Division of Pulmonary and Critical Care at the University of California, San Francisco who is establishing himself as a basic translational investigator of the immunology of acute lung injury. This K08 award will provide Dr. Calabrese with the necessary support to accomplish the following goals: (1) to improve the understanding of natural killer (NK) cells, their receptors, and their ligands in ischemia-reperfusion injury, an important clinical problem (2) to acquire theoretical and practical skills in mouse immunology and bioinformatics (3) to define mechanistic pathways for future interventional trials to improve early lung transplant outcomes and (4) to establish an independent research career focused on innate immunity in lung injury. To achieve these goals, Dr. Calabrese has assembled a mentoring team consisting of his primary mentor, Dr. John Greenland, an international expert in lung transplant immunology and lung transplant rejection; a senior co-mentor Dr. Lewis Lanier, a member of the National Academy of Sciences and an expert in NK cell biology with over 50 prior mentees and 250 publications; Dr. Mark Looney, an expert in mechanisms of lung injury and mouse models of lung transplantation; Dr. Jonathan Singer, director ofthe UCSF lung transplant research program and an expert in lung transplant epidemiology research; and Dr. Dean Sheppard, Division Chief and expert in mechanisms of acute lung injury. Additionally, he will have tutorials and mentorship from Drs. Jason Christie, Dara Torgerson, Jeff Golden, Kirk Jones, Matthew Spitzer, and Michael Matthay in multi-institutional collaboration, statistical genetics, clinical trial design, lung pathology, mass cytometry, and human lung experimental models, respectively. The proposed research will expand on strong preliminary data in two established mouse models and human samples demonstrating a paradigm-shifting role of NK cells in pulmonary ischemia-reperfusion injury (IRI). The proposed study will test the hypothesis that NK cells traffic to the lung and mediate primary graft dysfunction (PGD) through receptor-specific interactions through the following specific aims: (1) Determine how NK cells are activated and induce mouse PGD (2) Determine how NK cells traffic to the lung during mouse PGD (3) Evaluate NK cell activation in human PGD. This work is innovative as these studies will make use of advanced mouse surgical models, next generation flow cytometry, and multiplex protein quantification to define a previously unexplored area, the role of NK cells in lung injury following lung transplantation. This research is significant as it will open the way to clinical intervention in PGD, advancing the 2018 joint NHLBI and American Association of Thoracic Surgery (AATS) Lung Transplant Working Group?s stated goals to develop novel precision therapies based on donor or recipient endotypes to prevent PGD. This work is broadly applicable as it will define the role of NK cell receptors and stress ligands in PGD. It may also identify therapeutic targets for other organ recipients and ischemic disease.
Lung transplantation is a common treatment for end-stage lung disease with poor long-term outcomes compared to other solid organ transplant populations. This research focuses on the study of natural killer cells in ischemia- reperfusion injury, which manifests as primary graft dysfunction in up to 1/3 of all lung transplant recipients. This study may lead to a better understanding of this disease process and novel diagnostic or therapeutic modalities.
