Chaperones, ROS systems, & IGF-1:Roles in vascular aging

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DESCRIPTION (provided by applicant): The major purpose of this proposal is to investigate the molecular mechanisms that regulate phenotypic changes that occur in blood vessel walls during aging in mice. The investigators will use several experimental animal models to investigate the roles of three physiologic regulatory systems that have each been shown to modify the response to stress. These include reduction in insulin like growth factor I (IGF-I) signaling, which in lower organisms has been shown to enhance the heatshock protein response to stress and the ability to survive oxidative stress as well as modifications of age related changes in multiple tissues. These studies will determine if this finding in lower organisms extends to mice and if a particular receptor subtype (e.g. growth hormone or IGF-I) mediates this response, A second system that will be examined is regulation of generation of reactive oxygen species. The roles of superoxide dismutase 1 and 2 (SOD-1 & 2) in altering vascular aging will be investigated by altering their expression as well as p47 phox and then determine the outcome on the aging vascular phenotype. The interactions between changes in these components and changes in IGF-I and CHIP function and how they modify the vascular aging response will be defined, Gene profiling will be used to identify other molecular changes that occur when ROS are increased. A third series of studies will investigate the role of molecular chaperones in controlling age-related changes in the vasculature. The role of CHIP, a modifier of the heat shock protein response to stress, in altering the response to ROS manipulation and in lesion formation will be investigated. The role of modifying these genes in altering the atherosclerotic response that occurs in response to vascular injury will be examined. Femoral arteries will be denuded and the atherosclerotic lesions that form after 14-28 days analyzed to determine the role of each of these components in lesion progression. Several types of genetically altered mice will be crossed with APOE deficient mice and the development of spontaneous hypercholesterolemic induced atherosclerotic lesions will be analyzed. The results should define the relationship between alteration of each of these signaling systems and both the development of the aging vascular phenotype and in neointimal formation. Since there are interactions between IGF-I signaling, ROS system generation and expression of CHIP in controlling both IROS production and IGF-I signaling, analysis of the interactions among each of these three systems may provide further insight into molecular mechanisms that regulate these changes in normal vessel walls and their roles in supporting neointimal formation.