Stroke is the second leading cause of death and a major cause of disability in the world. The currentgeneration of thrombolytic agents, such as tissue-type plasminogen activator (tPA), only benefit a limitednumber of the potential patients with ischemic stroke, and the development of improved therapies for thetreatment of stroke depends upon understanding the unique characteristics of the cerebrovasculature. Thelimited benefit of tPA may be due in part to unique activities that tPA has in the brain beyond its wellestablished role as a fibrinolytic protease. In particular, animal studies have indicated that tPA interacts withat least two different cellular receptors expressed in the brain, and these associations have been linked toboth neurotoxicity and altered blood-brain-barrier function. And while there are clear benefits to patents whoreceive early thrombolytic treatment, these recently described effects of tPA suggest that there are uniquechallenges for the use of thrombolytic therapy in ischemic stroke. Ideal treatments for ischemic stroke wouldsimultaneously promote the reestablishment of vascular patency, inhibit the development of cerebral edema,reduce the incidence of hemorrhagic transformation, and provide direct neuroprotection. Our previousstudies have shown that the natural inhibitor of tPA in the CNS, neuroserpin, appears to act as aneuroprotective agent that can promote significant neuronal survival and cell recovery after stroke. Inaddition our studies suggest that antagonism within the CNS of the tPA receptor, the LDL Receptor RelatedProtein (LRP), dramatically reduces blood-brain-barrier dysfunction following stroke. Thus, this proposal willtest the hypothesis that during cerebral ischemia tPA, neuroserpin, and LRP function together within thebrain to regulate blood-brain-barrier permeability and neuronal survival. We will investigate the mechanismsof this regulation, and test the hypothesis that targeting these interactions will lead to the development ofmore effective therapies for the treatment of ischemic stroke. We will also evaluate novel treatments forstroke by combining various thrombolytic and neuroprotective agents, and comparing the efficacy of thesecombined therapies in murine models of stroke.
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