The goal of our proposal, """"""""Oxidative Stress and Vascular Aging"""""""" (Project 1), is to investigate the interaction between aging and reactive oxygen species (ROS) in atherogenesis. It is well known that the prevalence of coronary artery disease increases with age, and that age itself is an independent risk factor for atherogenesis. However, specific molecular events in aging that are conducive to atherosclerotic lesion formation remain to be elucidated. We hypothesize that factors that alter ROS production in smooth muscle cells (SMCs) cause cellular and vascular dysfunction in both aging and atherosclerosis. The proposal is divided into four aims that synergistically integrate with Projects 2 and 3 and the Cores described in this application. These studies will utilize a number of experimental mouse models. Based on data from our group and others, mice provide an excellent model for understanding the intrinsic effects of aging on vascular wall biology that contribute to the atherogenic process. In addition, the relationships between ROS generation, vascular cell phenotypes, and atherosclerotic lesion formation are well suited for study using in vitro and in vivo mouse models. Having previously established an association between aging, ROS production, and atherosclerotic lesion formation, we will now begin to explore the molecular events that link these processes in the present proposal.
In specific aim 1, we will quantify the impact of increased and decreased ROS production on the vascular phenotypes of aged mice. The second specific aim describes experiments in which we will characterize the proliferative phenotypes and signaling pathways activated in aged SMCs with altered ROS metabolism. Given our prior demonstration that cell cycle entry is attenuated in SMCs from aged mice (even though these cells produce increased ROS), we will explore the molecular events that mediate this disparity, with a focus on signaling and transcriptional events in specific aim 3. Finally, in the fourth specific aim we will characterize the ROS-dependent and ROS-independent transcriptional profiles of SMCs from aged mice. We believe that these experiments, in the context of this Program Project Application, will allow us to identify the specific ROS-dependent and ROS-independent intracellular signals and transcriptional pattems that underlie long-term, age-related changes in SMC phenotype and, further facilitate the development of strategies to limit the atherosclerotic burden associated with aging.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1)
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University of North Carolina Chapel Hill
Chapel Hill
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