Effect of sarcolemmal KATP channels on ROS/RNS generation and calcium handling

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SPACE PROVIDED. Cardiovascular Disease is the leading cause of morbidity and mortality in the United States. As stated above it is imperative that vve understand the mechanisms responsible for ischemic heart disease so that more effective therapies can be designed. This award will expand the Principal investigator's (PI) skills and develop his academic career in Cardiovascular Ischemia-Reperfusion Medicine by combining a career plan to supplement his knowledge base with laboratory rotations with experts in the field. The PI is a Ph.D/M.D. with advanced research and clinical training in Cardiovascular Medicine and Interventional Cardiology. Mentored by Dr. Jay Zweier, a recognized world leader in ischemia-reperfusion injury, magnetic resonance imaging techniques and oxidative biology, and Dr. Muthu Periasamy, a world leader in myocyte biology and calcium handling, and Dr. Elizabeth Murphy, a world leader in myocardial ischemia-reperfusion biology and sex-differences, the PI will perform studies using the unique resources available within Davis Heart and Lung Research Institute (DHLRI) and The Ohio State University Biomedical Spectroscopy and Imaging Center. The importance of understanding the mechanisms responsible for ischemic heart disease was highlighted by the report of the NHLBI Working Group on the Translation of Therapies for Protecting the Heart which recognized that "fundamental gaps in knowledge remain that limit the effective translation of cardioprotective therapies from experimental to clinical settings." This research program will investigate the role of the sarcolemmal ATP-sensitive potassium channel (sarc-KATp) in susceptibility to ischemia-reperfusion (l/R) injury, examining specifically the effect on calcium handling and the generation of reactive oxygen species and reactive nitrogen species using physiological, biochemical, molecular and EPR techniques that are uniquely available within the Zweier lab and The Ohio State University EPR imaging center. The specific aims are to examine the sexual dimorphisms observed with KATP channel knockout with respect to : (1) The effect of sarc-KATP channel activity on in vivo formation of reactive oxygen and nitrogen species (ROS, RNS) and tissue oxygenation during myocardial ischemia-reperfusion injury, and (2) The effect of sarc-KATP channel expression on calcium handling protein levels, activity, and S-nitrosylation in response to ischemia- reperfusion injury in vivo and ex vivo. The availability of world-class EPR-based imaging technologies at The OSU, the outstanding expertise of the Mentor and Advisory Committee, and the qualifications ofthe PI provide an excellent atmosphere for success in the program described. This research will provide critical understanding ofthe mechanisms by which sarc-KATP channels influence the susceptibility to myocardial ischemia-reperfusion injury.