Oxidative stress generated during cerebral ischemia and reperfusion is a critical event leading to damage of the neurovascular unit that causes blood-brain barrier disruption, with secondary vasogenic edema and hemorrhagic transformation of infarcted brain tissue, restricting the benefit of tissue reperfusion with thrombolytic agents. However, little is known about the cellular and molecular mechanisms and signaling pathways that underlie oxidative stress in the damage of the neurovascular unit that consists mainly of endothelial cells, astrocytes, and neurons. Our working hypothesis is that NADPH oxidase, a pro-oxidant enzyme that localizes in all the cells of the neurovascular unit, initiates oxidative stress and downstream signaling that cause neurovascular damage and intracerebral hemorrhage in the stroke brain. This Program consists of three interactive projects and two supporting cores. Project 1 is to investigate the role of endothelial NADPH oxidase in oxidative stress, endothelial cell damage, and intracerebral hemorrhage. Project 2 will elucidate the role of the interplay between hyperglycemia and oxidative stress generated by NADPH oxidase in ischemic neuronal injury. Project 3 will elucidate astrocytic HSP70 and NADPH oxidase in endothelial protection and injury in the ischemic brain. We believe these are novel studies that will provide insights into the oxidative mechanisms in neurovascular dysfunction after cerebral ischemia. The long-term goal of these studies is to develop therapeutic interventions that target neurovascular function for stroke patients.
Lay statement: Most strokes are caused by occlusion of the cerebral artery by a thrombus (ischemic stroke). Early restoration of cerebral blood flow (reperfusion) with a thrombolytic agent or spontaneous reperfusion can salvage brain tissue, but can also have a deleterious effect by generating reactive oxygen species by NADPH oxidase. The latter can further damage neurons and vessels. This Program aims to elucidate the role of NADPH-oxidase in reperfusion injury and to provide strategies to prevent or to ameliorate brain damage in patients with acute stroke.
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