Purinergic Modulation of NKT Cells Ameliorates Hyperoxic Lung Injury

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High inspired concentrations of oxygen are commonly administered to critically ill patients or during perioperative management (especially in thoracic and cardiac surgery). However, increasing evidence suggests that pulmonary hyperoxia may promote inflammation, lung injury and worsen patient outcomes. Under the combined mentorship of Dr. Simon C. Robson, Professor of Medicine at Harvard Medical School, and Dr. Holger Eltzschig, Professor of Anesthesiology at University of Texas, the candidate will investigate novel therapeutic approaches to mitigate against acute hyperoxic lung inflammation. We have previously identified key roles for natural killer T cells (NKT) in mediating hyperoxic lung injury. Novel therapeutic approaches studied in this proposal are based on purinergic modulation of NKT cells and potentially other immune cells involved in lung injury, which we found can be achieved by targeting two closely related ectoenzymes CD39 (ENTPD1) and autotaxin (ENPP2). These approaches are operational, at least in part, by increasing levels of extracellular ATP (promoting NKT cell apoptosis) and/or decreasing levels of lysophosphatidic acid (LPA) which is a key NKT cell growth factor. We hypothesize that catalytic activities of these ectonucleotidases/phospholipases - CD39 and autotaxin - dictate recruitment of NKT and other immune cells that then cause alveolar injury by modulating the phospholipid- phosphonucleotide milieu. In the first aim, involvement of immune subsets in hyperoxic lung injury will be characterized by time of flight mass cytometry-CyTOF and systems immunology approaches. In the second aim, we will investigate the precise mechanisms by which CD39 and ATX targeting modulates lung injury. In the third aim, novel translational approaches of autotaxin and CD39 targeting in acute lung injury in vivo, including in humanized mouse model, will be studied. The candidate is an anesthesiologist and intensivist at Massachusetts General Hospital and is committed to the pursuit of an academic career in translational investigation. Mentorship by basic scientists and clinicians during this award will allow him to develop skills and expertise necessary to lead an independent research program. Pilot investigations of NKT and other invariant cells in patients with lung injury will be a component of career development plan and provide the basis of future grant applications. The candidate’s immediate goal to acquire robust research skills, as related to inflammation and acute lung injury, is reflected in the proposed research and in his choice of mentors and collaborators. The primary mentor, Dr. Simon C. Robson, MD PhD is a renowned international expert in inflammation and purinergic signaling. The co-mentor, Dr. Holger Eltzschig, MD PhD, is a leader in perioperative organ protection research and has worked with Dr. Robson over the past decade. Collaborators include Leo Otterbein, PhD (models of lung injury), James Lederer, PhD (CyTOF) and John Asara, PhD (metabolomics). Success with this NIH career development application will allow Dr. Hanidziar to develop an innovative research program, bridging immunology and critical care and to launch his career as a wholly independent investigator.