Despite recent advances in prevention and therapy, stroke remains the leading cause of long-term disability and the third most common cause of death in the United States. A major conceptual advance in understanding the pathophysiology of stroke was the identification of two distinct stages of disease progression: primary tissue damage in the ischemic core, and secondary tissue injury in the surrounding penumbra. The inflammatory response elicited by cerebral ischemia is a promising target for pharmaceutical intervention of stroke, because it progresses over many hours after stroke, and exacerbates tissue injury. As a feedback regulatory mechanism, an endogenous ubiquitous molecule, spermine, accumulates at sites of injury, and inhibits the release of various proinflammatory cytokines. Sperminemediated immune suppression is dependent on the negative acute phase protein, fetuin, which is significantly increased in the brains of animals subjected to experimental cerebral ischemia (middle cerebral artery occlusion, MCAO). Furthermore, peripheral administration of exogenous fetuin immediately after MCAO confers dose-dependent protection against cerebral ischemic injury at 24 hours after MCAO. Several important questions remain unanswered regarding the long-term neuroprotective efficacy of fetuin, and the mechanisms underlying ischemia-elicited elevation of brain fetuin levels, as well as the fetuin-mediated neuroprotection against cerebral ischemic injury. We will first determine the long-term effects of inhibiting (by intracerebral administration of fetuin-specific antibodies or genetic disruption of fetuin expression) or augmenting (by intravenous or intracerebroventricular administration of exogenous fetuin) cerebral fetuin levels on cerebral ischemic injury (Specific Aim 1). To delineate the mechanisms underlying ischemia-induced increase of brain fetuin levels, we will determine whether fetuin in the ischemic brain tissue is produced locally by the central nervous system, or obtained (across the blood-brain barrier) from the peripheral circulation (Specific Aim 2). Lastly, we will delineate the specific mechanisms of fetuin-mediated neuronal protection by determining whether administration of fetuin alters expression of proinflammatory cytokines (such as TNF and HMGB1), or animal physiological parameters such as blood pressure and organ perfusion (Specific Aim 3). Answers to these questions will improve our understanding of the pathophysiology of ischemic neural injury, and identify novel therapeutic agents for the treatment of stroke and related disorders.
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