Many investigators have suggested that a common pathway to macromolecular changes and cell degeneration is through the production of reactive oxygen species (ROS) and their reactions with DNA, proteins, and cell membranes. Thus, the loss of normal macromolecular, cellular and organ function in senescence is, at least in part, the result of the cumulative effects of oxidative stress, i.e., of an altered balance between oxidants and antioxidants in cells. The central hypothesis being advanced in this proposal is that during aging of cells there is a cumulative oxidative modification of macromolecules that play important roles in the regulation of ionic fluxes, especially Ca2+, across biological membranes. These proteins are the Ca2+- and H+-transport proteins in muscle cells and neurons, the Ca2+- dependent regulatory protein calmodulin in erythrocytes, cardiac muscle cells and neurons, and the Ca2+-conducting N-methyl-D-aspartate receptor- ion channels in neurons. It is proposed that the oxidative modifications of these proteins occurs at specific sites that are predictable based on the amino acid structure of each protein. It is further proposed that the changes in structure, function or turnover of the cognate proteins in cells obtained from an aging organism are a reflection of such ROS-induced modifications. There are 6 projects included in this Program Project, each dealing with different aspects of the general hypotheses advanced above. These projects are: 1. Protein oxidation by ROS: Relation to Aging. 2. Calmodulin, aging, and calcium homeostasis. 3. Aging and oxidation in skeletal and cardiac muscle. 4. Oxidative stress, aging, and brain Ca2+ transporters. 5. Neurotoxicity, NMDA receptors, and free radicals. 6. Oxidative stress in brain neurons during aging. Since the hypothesis being advanced in project #6 is not proven, funding is requested for this project for an initial period of two years. All of the other projects are described for the full period of the proposed program of research. The administrative core (Core A) is designed to coordinate the research and management aspects of the proposed program whereas a scientific core (Core B) will be dedicated to the development of highly sensitive analytical methods to identify specific peptide and amino acid modifications in proteins expressed in relatively low abundance in animal and human tissues.
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