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Hypothermia for Cardiac Arrest: Optimizing Akt-Nitric Oxide Synthase Signaling

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This proposal is a natural extension of the candidate's background in Emergency Medicine and Biomedical Engineering. His unique background and passion for translational science has already contributed to animal resuscitation research. This innovative work models early post-cardiac arrest reperfusion injury in our patients, i.e. cardiovascular collapse despite initial return of spontaneous circulation (ROSC). The training program will enhance the mouse modeling already done by formally training the applicant in the best molecular biology approaches for study of nitric oxide signaling and uncoupling. The applicant will benefit from multi-disciplinary mentorship within the Emergency Resuscitation Center, building upon expertise in heart oxidant injury and adaptation, and free radical biology. The sponsors Drs. Vanden Hoek and McNally are experienced physician-scientists. They are also collaborators interested in oxidantmediated heart contractile dysfunction and death in cardiomyocyte and mouse models. This Career Development Project builds upon the strengths of the applicant, the training program and institutional support and mentorship. We hypothesize that protective hypothermia following cardiac arrest increases Akt-related constitutive nitric oxide synthase (cNOS) NO-signaling, while attenuating cNOS uncoupling and generation of damaging reactive oxygen species (ROS). Specifically, in a mouse model of cardiac arrest we will: (Aim 1) Optimize the target temperature of protective hypothermia based on heart Akt and cNOS activity; (Aim 2) Test the relative importance of NOS1/NOS3 in post-cardiac arrest injury, NO and ROS generation, and hypothermia protection using selective-inhibitor and knockout strategies; and (Aim 3). Test whether hypothermia protection can be reproduced by NOS substrate/cofactor repletion strategies. The University of Chicago Department of Medicine and Section of Emergency Medicine have a track-record of successful mentoring using the K08 physician-scientist training program. The proposed training will provide Dr. Beiser with additional skills to become a leading independent physician-scientist in his field. From a layperson perspective, cardiac arrest (when the heart stops) is different than depicted on TV or the movies-most people initially resuscitated do not survive. This work will help understand how cooling the body a few degrees can actually increase a type of oxidant stress that helps the body heal itself.
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