OXIDATIVE STRESS INDUCED APOPTOSIS IN CARDIAC MYOCYTES

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DESCRIPTION (Adapted from applicants' abstract) The applicant's long term career goal is to contribute at a basic level to our understanding of the molecular mechanisms of heart failure. His short term career objectives are: 1) to gain insight into and learn techniques available for the measurement and manipulation of reactive oxygen species (ROS) in living systems; 2) use various molecular biological techniques for the manipulation and measurement of transcriptional events in cultured myocytes; 3) and then use in vivo animal models of myocardial injury and transgenic animals to test hypotheses developed in culture systems. The candidate received his Ph.D. in 1990 studying lipid protein interactions using single channel electrophysiology, and has spent the last 5 years at Brigham and Women's Hospital completing my clinical training in internal medicine and cardiology. There he began to study the mechanisms of ROS mediated myocardial injury, specifically, programmed cell death. He recently moved to Boston Medical Center to continue these efforts. The particular interest of cardiology and medicine faculty there in ROS provides a fertile environment for him to develop his scientific ideas. The hypotheses he will test are that ROS, in particular superoxide anion and/or hydroxyl radicals, can trigger apoptosis in ventricular myocytes, and that myocytes are able to regulate their susceptibility to these species by transcriptional regulation of cytotoxic defense systems. Firstly, he will use cultured adult and neonatal rat ventricular myocytes to examine exactly which ROS can induce apoptosis in cultured myocytes. Secondly, he will examine whether preconditioning stimuli can increase activities of specific cytotoxic defense systems and in this way prevent ROS-mediated apoptosis in ventricular myocytes. Thirdly, using an adenovirus transfection system, he will study whether over-expression of superoxide dismutase or catalase can protect against ROS-Induced apoptosis in cardiac myocytes. Finally, he will examine whether transgenic mice over-expressing manganese-dependent superoxide dismutase have increased susceptibility to myocardial apoptosis after myocardial infarction.