Nitrite based neuroprotection after cardiac arrest

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DESCRIPTION (provided by applicant): Dr. Dezfulian is an adult and pediatric critical care physician acutely aware of the paucity of post-resuscitation therapies for the cardiac arrest survivors he cares for. This career development award supplements his research background with senior mentorship and lab-based and didactic training in neurosciences and redox signaling. The research plan is based on preliminary observations which support the hypothesis that nitrite-mediated neuroprotection after cardiac arrest occurs through nitric oxide (NO) and S-nitrosothiol (S-NO)-based signaling that prevents subsequent neuronal death by targeting delta protein kinase C and mitochondria. This hypothesis will be tested along three aims: (1) to define the optimal nitrite dose and timing and quantify the relative contributions of NO- and S-NO based signaling in neuroprotection, (2) to test whether nitrite-mediated neuroprotection results from nitrosylation and inactivation of delta protein kinase C (-PKC), and (3) to test whether nitrite-mediated NO and S-NO production affects mitochondrial function and prevents apoptosis. Dr. Dezfulian will undertake a career development plan consisting of: 1. Experimental research, laboratory instruction, journal clubs and scientific review and development by his mentors and colleagues. 2. Coursework through the University of Miami graduate program. 3. Intramural seminars and national conferences and symposia. 4. Training in the responsible conduct of research. 5. Guidance by a scientific advisory committee consisting of two senior MDs and two PhDs. 6. Grant writing, grant review and development of a transition plan aimed at independence. Dr. Dezfulian's neuroscience mentorship will primarily come from Dr. Miguel Perez-Pinzon, CVDRC director. Dr. Perez-Pinzon is an accomplished NIH-funded neuroscientist who studies mechanisms of neuroprotection and mitochondrial dysfunction after brain ischemia. Dr. Dezfulian will be co-mentored by Dr. Joshua Hare, Director of the Interdisciplinary Stem Cell Institute (ISCI). Dr. Hare is NIH-funded to investigate oxidative stress in heart failure, has a long track record of research in nitroso-redox signaling, and will provide guidance regarding key mechanistic pathways believed to underlie nitrite mediated neuroprotection. This mentorship team will guide Dr. Dezfulian's career development as he executes the research aims of this application and transitions to independence as a clinician scientist. PUBLIC HEALTH RELEVANCE: This career development awards provides Dr. Cameron Dezfulian, an intensive care unit physician, with salary and research support to pursue a career development plan aimed at making him an independent clinician scientist studying ways to reduce brain injury after cardiac arrest. Dr. Dezfulian will be mentored by two senior scientists at the University of Miami and conduct research aimed at discovering new ways to signal protection in brain after cardiac arrest to prevent the brain injury that normally results.