The regulation and function of platelet FcARIIA in sepsis

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PROJECT SUMMARY/ABSTRACT This is an application for a K08 award for Dr. Elizabeth Middleton, a pulmonary and critical care physician at the University of Utah. Dr. Middleton is establishing herself as a young investigator in translational research of biological mechanisms driving the pathophysiology of sepsis. Her long-term goal is identification of new therapeutic targets to advance the care of patients suffering with sepsis so they have longer and have improved quality of life. The role of platelets in inflammation and infection is poorly understood. She is proposing to investigate the contribution of the megakaryocytes (the platelet parent cell) and platelets, and how they impact a patient’s response to sepsis. This K08 will provide Dr. Middleton with the support necessary to accomplish the following goals: 1) gain expertise in megakaryocyte (MK) biology, gene expression, and functional assessments, 2) to increase knowledge of platelet FcγRIIA biology and function through use of humanized transgenic mouse model, 3) to develop the skills and toolsets to dissect intracellular platelet signaling events, 4) expand skills to independently lead and manage a translational research program. To achieve these goals, Dr. Middleton has assembled a mentoring team comprising a primary mentor, Dr. Matthew Rondina, an established physician-investigator and leader in the field of platelet biology in immune responses and inflammation, and 4 advisors who are leaders in the fields of megakaryocyte gene expression, biology and function, translational research in sepsis and acute respiratory distress syndrome, and genetically altered murine research. The primary treatment for sepsis is early recognition and hemodynamic resuscitation, antibiotics and supportive care. Despite hospital-based systems to detect the onset of sepsis, it continues to carry significant mortality, short- and long-term morbidity. Dr. Middleton’s research focuses on the study of a platelet immune receptor, Fc fragment of IgG receptor IIA (FcγRIIA), which is positioned at the cross-roads hemostatic, immune, and inflammatory continuum. Dr. Middleton will (Aim 1) determine how platelet FcγRIIA expression is increased in sepsis; (Aim 2) determine if increased platelet FcγRIIA during sepsis causes hyperactivation, thrombosis, and mortality. In Aim 1, Dr. Middleton will investigate the inflammatory agonists that drive increases in platelet FcγRIIA and track the expression of this receptor from the megakaryocyte to circulating platelets. In Aim 2, Dr. Middleton will interrogate whether the increased platelet FcγRIIA contributes to risk of thrombosis and short-term mortality associated with sepsis. This research will prepare Dr. Middleton to design and implement a research program with clinical applicability to inform future therapies for sepsis.