This application represents a request for continued support of the Program Project Grant entitled "Arterial dysfunction: basic and clinical mechanisms", which has had continued NHLBI support since 1992. A unifying concept in this renewal application is the investigation of pathophysiological mechanisms of endothelial cell metabolism and oxidative stress that modify critical pathways in endothelial cells leading to arterial dysfunction. This research program unites the efforts of investigators working in basic and translational science laboratories at Brigham and Women's Hospital. Discoveries by the Project Leaders and by others in the field have led to the identification of the vascular endothelium as a key modulator of organismal metabolism, along with a growing understanding ofthe role of redox-modulated pathways in the control of vascular function. Oxidative stress represents a common feature of vascular disease states, yet the molecular mechanisms that modulate cellular redox balance in normal and diseased vascular tissues remain incompletely understood. The focus in this renewal application is on achieving a greater understanding of the pathophysiology of arterial dysfunction with a focus on endothelial cells as a gateway for metabolic control pathways that are dynamically modulated by redox pathways. The Project Leaders for this renewal application represent a cohort of experienced investigators in vascular biology. Project 1, "Redox regulation of eNOS signaling pathways in vascular endothelium", is led by T. Michel, who also directs the "Animal models of redox metabolism and vascular dysfunction" Core. Project 2, "The endothelial PPARy-RXR transcriptional complex in the control of metabolism", is led by J. Plutzky;R. Lee leads Project 3, "Thioredoxin-interacting protein in endothelial and organismal metabolism". J. Loscaizo leads Project 4, "Glutathione peroxidase-1, mitochondrial function, and endothelial phenotype", and also is Co-Director of the Redox Biochemistry Core, which is directed by V. Gladyshev. P. Libby directs the Redox Biomarkers Core;metabolic characterizations of mouse models studied in this Program will take place at the Yale Mouse Metabolic Phenotyping Center, led by G. Shulman.
Many cardiovascular diseases are characterized by oxidative stress pathways that lead to arterial dysfunction. The research projects in this Program Project Grant are led by experienced vascular biologists and biochemists who have identified a common experimental theme exploring the role of oxidative stress on pathways leading to vascular disease and to metabolic abnormalities.
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