Inhibition of ERK1/2 Signaling for Spinal Cord Injury

  • Geddes, James (PI)

Grants and Contracts Details


Overactivation of extracellular signal-regulated kinases 1 and 2 (ERK1I2) is implicated in pathology of brain and spinal cord injury (SCI). ERK 1/2 cascades target many secondary injury components including NMDA receptors, calcium-activated neutral cysteine proteases (calpains), matrix metalloproteinase-9 (MMP-9), caspase3, NK-lR, and nucleic factor KB (NF-KB). Inhibition ofERKl/2 results in significant neuroprotection from ischemic injury, however, there are also conflicting reports regarding ERK1/2 inhibition and traumatic brain injury. Little is known regarding the contribution of ERK 1/2 activation to pathological and functional outcomes following contusive spinal cord injury (SCI), the focus of this proposal. Specifically we will evaluate the hypothesis that inhibition of ERKl/2 signaling significantly reduces tissue damage and improves locomotor function following SCI. Previously, we demonstrated that ERKl/2 inhibition prevents the onset of pain-related behavior following excitotoxic SCI. In the proposed study we will first utilize a pharmacological inhibitor SL327, which inhibits the ERK1I2 activator MAP kinase kinase (MEK), on tissue damage and locomotor deficits following experimental contusion SCI. We further hypothesize that ERK2 activation is predominantly involved in pathology of neurodegeneration, while ERK 1 activation is responsible for neuroprotection following SCI. Isoform specific inhibitors of ERK I vs. ERK2 are not available. Therefore, we will utilize lentiviral vectors encoding ERK2 shRNA to selectively knock-down ERK2 and evaluate the effects on tissue damage and locomotor function after contusion SCI. In our preliminary studies, we have validated the gene silencing efficiency of synthetic ERK2 siRNA in PC 12 cells. The long term goal of the proposed study is to evaluate ERK1/2 inhibition as a otential therapeutic target following contusion SCI.
Effective start/end date5/1/0610/31/07


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