Project Summary/Abstract The goal of this Mentored Career Development Award is to facilitate the primary investigator's transition to independence as a physician-scientist studying the molecular mechanisms underlying brain injury that occurs after a cardiac arrest. The candidate is a MD/PhD critical care physician and anesthesiologist with a background in neurodegenerative and brain injury research. The award will help the candidate gain research experience in the analysis of neuronal cell death pathways and brain inflammation, measurement of synaptic function, and assessment of cognition in mouse models of cardiac arrest. The environment in which the proposed research will be conducted is outstanding, and includes structured mentorship from neuroscientists and physician-scientists with diverse backgrounds. The candidates mentor and co-mentor, Dr. Nidia Quillinan and Dr. Elizabeth J. Kovacs, are well-respected experts in the fields of cardiac arrest, global cerebral ischemia, aging research, and inflammation. The proposed research will investigate the role of inflammasome pathways as molecular mediators of age-related differences in brain injury after global cerebral ischemia induced by a cardiac arrest. The incidence of cardiac arrest dramatically increases with age, with older survivors having a worse neurologic prognosis and poor response to post-arrest care. A potential cause of worsening brain dysfunction after a cardiac arrest in older individuals is age-associated inflammation (inflammaging). Activation of the inflammasome multi-protein complex is a primary driver of inflammaging and has been shown to mediate cognitive deficits in both brain injury and disease. The goal of this project is to test the hypothesis that global cerebral ischemia results in a more robust and sustained inflammasome activation with advanced age that results in increased cell death and synaptic deficits in survivors. In order to test this hypothesis, the primary investigator will use a murine model of cardiac arrest and cardiopulmonary resuscitation (CA/CPR) to (Aim 1) assess for age-related differences in inflammasome-mediated inflammation after global cerebral ischemia and (Aim 2) evaluate the extent to which inflammasome activity contributes to CA/CPR induced neuronal cell loss, acute deficits in synaptic function, and cognitive impairment in young and advanced age mice. The proposed experiments are designed to elucidate a novel aging-relevant molecular mechanism involved in the brain's response to global cerebral ischemia. This career development award will provide the primary investigator with valuable research training relevant to the realms of ischemia, aging biology, and inflammation that will complement his clinical management of cardiac arrest survivors in the intensive care unit, and ultimately provide a skill set for the translation of basic science discoveries into novel therapeutic strategies for patients that suffer a cardiac arrest.