The overall goal of this project is to understand the molecular mechanisms of ischemic tolerance in cortical neurons. Neuronal ischemic preconditioning or tolerance is a phenomenon in which brief episodes of ischemia protect against the lethal effects of subsequent periods of prolonged ischemia. The signaling mechanisms leading to preconditioning are poorly understood but have the potential for providing important pharmaceutical targets for the treatment of patients at risk for ischemic injury and possibly the treatment of patients suffering from chronic neurodegenerative diseases such as Parkinson's Disease. Ischemia can be modeled in vitro by oxygen-glucose deprivation (OGD). We have recently discovered that OGD preconditioning induces p2 p21ras (Ras) activation in a NMDA receptor- and NO-dependent manner. OGD preconditioning is dependent on Ras activation of the Raf-Mek-Erk pathway. Our observations indicate that activation of the Ras/Erk cascade by NO is a critical mechanism for the development of OGD tolerance in cortical neurons, which may also play an important role in ischemic preconditioning in vivo. To further our understanding of preconditioning it is essential to identify the transcriptional elements that are activated and the new proteins that are responsible for this remarkable neuroprotection. In this project we propose to investigate the role of transcriptional targets of the Ras/Erk signaling cascade with a focus on CREB and Elk activation. We will identify genes that are regulated by preconditioning and determine which genetic changes are responsible for preconditioning. Preconditioning can also be induced by potassium depolarization in an in vitro model of spreading depression. We will investigate whether similar or different mechanisms are responsible for potassium depolarization induced tolerance. We anticipate that this series of investigations will identify endogenous protective mechanisms that ultimately may be harnessed as novel protective strategies against ischemic and traumatic injury as well as chronic neurodegenerative disorders such as Parkinson's Disease.
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