The last two decades have witnessed a significant decrease in acute ischemic stroke mortality, that in turn has caused a substantial increase in the number of patients that survive an ischemic stroke with different degrees of disability. Unfortunately, despite the magnitude of this problem, to this date the mechanisms that underlie the process of neurorepair following an ischemic injury are poorly understood, and there is no effective therapeutic strategy to promote neurological recovery among ischemic stroke survivors. Cerebral ischemia has a harmful impact on synaptic structure and function associated with the development of neurological deficits. Hence, neurological recovery following an ischemic stroke requires the formation of new synaptic contacts and/or the repair of those damaged by the ischemic injury. This is a highly dynamic process that begins with the reestablishment and/or de novo formation of adhesive contacts between axonal boutons and postsynaptic terminals, and is mediated by the interaction between membrane-bound adherent proteins. Neuronal cadherin (N-Cadherin or NCAD) is an adherent protein abundantly found in the synapse, where it forms adhesive contacts between the pre- and postsynaptic terminals. Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to its receptor (uPAR) catalyzes the conversion of plasminogen into plasmin and activates cell signaling pathways that promote cell survival, proliferation and motility. In the previous funding cycle of this application we found that uPA is released from the presynaptic terminal of cerebral cortical neurons during the recovery phase from an ischemic stroke, and that binding of this uPA to its receptor (uPAR) promotes the repair of axons and dendrites damaged by the ischemic injury. In this renewal application we will test the hypothesis that binding of either endogenous or recombinant uPA to uPAR promotes synaptic repair by inducing the formation of NCAD-mediated adhesive contacts between the pre- and postsynaptic terminals that have been damaged by an ischemic injury. To accomplish this goal, first we will study the mechanism whereby uPA regulates the expression and function of NCAD in the synapse, and test the hypothesis that uPA promotes synaptic recovery by inducing NCAD-mediated reestablishment and/or formation of new adhesive contacts between axonal boutons and postsynaptic terminals of neurons that have suffered an ischemic injury. Then, we will investigate the effect of uPA on the canonical Wnt-?-Catenin pathway. Finally, we will use an animal model of cerebral ischemia to investigate if uPA-induced NCAD-mediated activation of the Wnt-?-Catenin pathway promotes synaptic repair and neurological recovery after an ischemic injury.
Cerebral ischemia is a leading cause of disability in the world. Unfortunately, to this date there is no effective therapeutic strategy to promote recovery after an ischemic stroke. Here we will study a novel hypothesis that may lead to the development of a pharmacological tool to repair the brain that has suffered an ischemic injury.
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