The program project has two objectives. The first is the identification of the functional and structural mechanisms responsible for reactive metabolite-induced lethal cell injury. The goals of Project I, """"""""Final Common Pathway for Reactive Metabolite Injury: Abnormal Ca2+ Homeostasis,"""""""" are to complete the work in progress documenting that lesions at calcium regulatory sites mediate reactive metabolite-induced hepatic necrosis (acetaminophen, bromobenzene, CC14, diquat) and to investigate the role of changes in membrane calcium permeability versus calcium- ATPase activity in the plasma membrane and endoplasmic reticulum lesions. The goals of Project II, """"""""Chemical mechanisms of Lipid peroxidation and Thiol Oxidation in Oxidative Reactive metabolite Injury,"""""""" are to define chemically the mechanisms of lipid membrane peroxidation and protein thiol oxidation after diquat and acetaminophen, to determine the effects of diquat-initiated, reactive oxygen-mediated hepatic necrosis on hepatic iron complexes and metabolism in vivo and to determine the effects of desferrioxamine and ferrous sulfate of these parameters. The goals of Project III, """"""""Studies of Alkylating Reactive Metabolites Using Novel Mass Spectrometric Techniques,"""""""" are to characterize the structure of peptide adducts and reaction mechanisms of substituted furans and to utilize this knowledge to elucidate principles for the covalent binding of electrophiles based on the """"""""hardness"""""""" of their electrophilicity and on their ability to serve as substrates for GSH-S-transferases. The goals of Project IV, """"""""Oxygen Metabolite-Initiated Injury in Oxygen Therapy and in Ischemia- Reflow condition,"""""""" are to determine the presence of lipid peroxidation or protein thiol oxidation products and their pathogenetic importance is reactive oxygen injury and to determine the presence of vasoactive or chemotactic eicosanoid products and the pathogenetic importance of reactive oxygen serving as a calalyst to stimulate or modulate eicosanoid formation. The second objective of the PPG is the transfer of basic discoveries and methodologies in Projects I-lV to clinical investigation and applications in experimental therapeutics (Project V: """"""""Oxygen Metabolite-Initiated Injury in Neonates;"""""""" Project VI: """"""""Oxygen Metabolite-Initiated Injury in Adult Critical Care Medicine;"""""""" Project VII: """"""""GSH Homeostasis and GSSG Reductase Inhibition after BCNU Therapy in Man""""""""). The knowledge obtained in the basic studies should provide important new insights into the fundamental mechanisms responsible for lethal cell injury by reactive metabolites. The clinical studies should demonstrate and define the relevance of these mechanisms for improved therapy of drug and ischemia-induced diseases.
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