Epo-dependent JAK2 Signaling in Painful Neuropathy

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EXCEED THE SPACE PROVIDED. While the pathogenesis of neuropathic pain states following peripheral nerve injury is dependent on many changes in the sensory neural axis, the initial molecular events leading to the activation of cells at the site of nerve injury are critical in protecting the structure and function of sensory systems. Local expression of inflammatory cytokines is upregulated in hypoxic nerve, and are clearly implicated in the development and control of neuropathic pain in degenerating neuropathies. Erythropoietin (Epo) is a hematopoietic cytokine regulated by hypoxia in both erythroid cells and CNS neurons, which has recently been shown to protect CNS neurons from apoptosis and ischemic death. We recently reported that Epo is upregulated at the site of peripheral nerve injury, specifically in Schwann cells, during the neuropathy caused by chronic constriction injury (CCI). Preliminary data in two animal models of neuropathic pain support our hypotheses that Epo inhibits both pain behaviors and DRG apoptosis by activating neuroprotective signaling cascades. We propose that the mechanism underlying these events includes retrograde transport of Epo colocalized with its receptor (EpoR) from the site of nerve injury to the DRG where phosphorylated JAK2, the tyrosine kinase associated with EpoR, activates neuroprotective signaling. We will test these hypotheses by injecting rhEpo locally during CCI neuropathy and L5 spinal nerve crush injury, and measuring apoptosis and pain behaviors. In both in vivo and in vitro experiments, we will preemptively administer an Epo binding antagonist that interferes with the function of Epo/EpoR, and a pharmacological inhibitor of JAK2 that prevents JAK2- mediated signaling. The experiments will provide new information on the basic mechanisms of nerve injury and pain, and therefrom, new rationale for development of novel neuroprotective strategies for preventing chronic neuropathic pain. PERFORMANCE SITE ========================================Section End===========================================