The metabolic syndrome is present in nearly a quarter of American adults and is associated with premature vascular disease, making it one of the most important public health problems of the 21st century. We propose to establish a Specialized Center of Clinically Oriented Research (SCCOR) in Vascular Injury, Repair, and Remodeling at Washington University. The central theme of our SCCOR is to define the physiological, cellular and molecular mechanisms linking metabolic syndrome with atherosclerotic vascular disease and rapidly apply this information to transform the care of people with the metabolic syndrome. The metabolic syndrome is characterized by obesity, insulin resistance and inflammation, but how these conditions cause vascular disease and whether weight loss affects the underlying mechanisms are unknown. We will translate fundamental mechanistic observations into improved care for people with the metabolic syndrome through six interactive projects involving humans. In Project 1, we examine the feasibility of modulating genotoxic stress in the metabolic syndrome by using a new anti-inflammatory strategy. In Project 2, we define how the syndrome affects aortic aneurysms by studying the relationships between inflammation, circulating reparative cells, and persistent aneurysm expansion following surgical repair and extend the novel anti-inflammatory strategy of Project 1 to aneurysm biology. In Project 3, we elucidate the role of inflammatory signaling pathways in atherosclerosis associated with the metabolic syndrome and the role of weight loss in these pathways. In Project 4, we determine if the carbohydrate content of weight loss diets affects systemic inflammation and endothelial function in the metabolic syndrome. In Project 5, we implicate macrophage-derived oxysterols in the inflammation of atherosclerosis and determine if circulating oxysterols are novel biomarkers for vascular disease affected by weight loss in the metabolic syndrome. In Project 6, we examine the relationships between the osteopontin gene and vascular remodeling associated with inflammation in metabolic syndrome and characterize how thBse relationships are affected by weight loss. Our long term objective is to improve the quality of life for people with the metabolic syndrome by creating a translational framework to generate novel treatments for vascular disease. The multidisciplinary approach described in this application is likely to decrease the morbidity and mortality caused by vascular disease in the nearly 50 million Americans with metabolic syndrome.
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