Institute of Environmental Health Sciences
(313) 577-6575 (Phone)
(313) 577-0082 (Fax)
Overproduction of reactive oxygen species (ROS) have been implicated as important pathogenic mediators in many clinical disorders such as hyperoxic lung injury and ischemia/reperfusion- and adriamycin (ADR)-induced cardiac damage. The function of the prototypic antioxidant enzymes, which include three isoforms of superoxide dismutase, catalase, and glutathione peroxidase, in protecting cells and animals against oxidant-mediated tissue injury has been studied quite extensively both in vitro in cultured cells and in vivo in a whole animal. However, the molecular and cellular mechanisms by which ROS cause tissue injury are not well understood. In other words, the biochemical and cellular pathways, that are initiated by the increased oxidative stress in the targeted tissues and that contribute to the injury, are not known. Since sulfhydryl proteins are targets for oxidative modification when cells are under oxidative stress, and inactivation of the catalytic functions of critical cellular proteins may lead to irreversible cellular damage, we hypothesize that oxidation of sulfhydryl groups of proteins may contribute to the pathogenesis of the above three models of oxidant-mediated injury. Toward this end, the current research in our laboratory is to define the role of the cytosolic and the mitochondrial isoforms of glutaredoxin (Grx1 and Grx2, respectively), a thiotransferase functioning in reductive cleavage of protein mixed disulfides, in antioxidant defense using both transgenic and knockout mice. The potential cellular targets that interact with and that are protected by Grx1 and Grx2 will also be defined by proteomics approaches.