This ISA application proposes to provide the applicant with release from teaching and administration responsibilities. The candidate's career goal is to become a leading researcher in the area of oxidative stress and heart diseases. In this application, the applicant plans to evaluate a protective mechanism against cardiac injury associated with reactive oxygen species (ROS) generating therapeutic agents. Many studies suggest that ROS are produced in vivo by a wide variety of agents and disease conditions, but the contribution to these ROS to development of cardiac injury is unclear. The hypothesis to be tested is that ROS generated in the mitochondria by therapeutic agents contribute to the cardiotoxicity of the therapeutic agents, and antioxidant enzymes modulate ROS-induced cardiomyopathy. To test this hypothesis, the expression of mitochondrial superoxide dismutase (MnSOD) and glutathione peroxidase (GPX) in heart tissue will be elevated by transgenic manipulations. The effect of ROS generating therapeutic agents on the heart tissue will be examined in transgenic mice expressing a range of MnSOD and/or GPX activity under experimental therapeutic conditions. The results obtained from this study should clearly demonstrate if increased mitochondrial antioxidant enzymes lead to protection of ROS mediated cardiomyopathy. The applicant is currently not only fully responsible for two courses but will also participate in a number of team-taught courses offered by the Graduate Center for Toxicology (GCT). In addition, the applicant serves on the committees of 17 graduate students, is a member of three administrative committees, and chairs the department's curriculum committee. With an ISA award, the applicant's teaching responsibility will be limited to one team-taught course in the subject of the research specialty. The applicant will also be relieved of 75% of her administrative duties. The redistribution of her effort will allow the applicant to concentrate on the research, including learning additional methodologies in cardiovascular research. As her most recent research has been focused on the molecular biology of antioxidant enzymes, the applicant has scheduled research at laboratories specializing in various aspects of cardiovascular research both at the University of Kentucky and elsewhere. The GCT will provide the applicant with research leave so that she can spend time at other institutions. Furthermore, the GCT will provide her with a post-doctoral associate position throughout the entire period of the award.
