Grants and Contracts Details
Description
Overactivation of extracellular signal-regulated kinases 1 and 2 (ERKl/2) is implicated in pathology of brain and
spinal cord injury (SCI). Although ERKl/2 signaling is typically associated with growth factors and neuroprotection, ERKl/2 is
activated following injury and targets many secondary injury components including NMDA receptors, calcium-activated neutral
cysteine protease (calpain), matrix metalloproteinase-9 (MMP-9), caspase 3, NK-lR, and nucleic factor kB (NF-kB). Inhibition of
ERKl/2 results in significant neuroprotection from ischemic and traumatic brain injury, however, there are also contrary reports
showing that ERKl/2 inhibition worsens brain injury. This proposal will focus on the contribution ofERKl/2 activation to contusive
spinal cord injury, where little is known regarding the timecourse and localization ofERKl/2 activation postinjury and the effects of
ERKl/2 inhibition on pathological and functional outcomes. These studies will be the focus of Aim 1 of our proposal. Previously, we
demonstrated that ERKl/2 inhibition prevents the onset of pain-related behavior following an excitotoxic spinal cord injury. It is also
important to identify the specific deleterious and beneficial effects of the two ERK isoforms on spinal cord injury. Based on the results
of previous studies, we hypothesize that ERK2 may be involved in pathology of cell death and axonal damage, while ERK 1 may be
necessary for cell survival and neurite outgrowth. Selective inhibitors ofERKl or ERK2 are not available. In Aim 2, we will test the
hypothesis that knockdown ofERK2 by delivery oflentiviral-shRNA following spinal cord injury will attenuate the deleterious effects
of the ERKl/2 cascade, reduce secondary damage, and improve locomotor function. Knockdown ofERKl is hypothesized to
aggravate spinal tissue damage, and worsen locomotor deficits following contusive spinal cord injury. In our preliminary studies, we
have validated the gene silencing efficiency of synthetic ERK2 siRNA in PC 12 cells and verified the efficacy of intraspinal delivery of
lentiviral-ERK2 shRNA into spinal cells in the rat. Our pilot data demonstrated that knockdown ofERK2 by lentiviral-ERK2 shRNA
pretreatment resulted in significant improvement in locomotor function, total spinal tissue sparing, grey matter sparing and white
matter sparing, compared with lenti-GFP injection. The specific aims of the proposed research are: (1) To test the hypothesis that
blockade ofERKl/2 activation is neuroprotective following spinal cord injury; and (2)to test the hypothesis that postinjury
administration oflentiviral-ERK2 shRNA will attenuate, while lentiviral-ERKI shRNA will exacerbate, spinal tissue damage, pain
behavior, and locomotor impairment following contusive spinal cord injury in rats.
Status | Finished |
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Effective start/end date | 1/15/08 → 1/14/15 |
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