Epo-dependent JAK2 Signaling in Painful Neuropathy

超出所提供的空间。虽然周围神经损伤后神经性疼痛的发病机制依赖于感觉神经轴的许多变化，但导致神经损伤部位细胞激活的初始分子事件对于保护感觉系统的结构和功能至关重要。炎症细胞因子的局部表达在缺氧神经中上调，并且显然与退行性神经病的神经性疼痛的发展和控制有关。促红细胞生成素（Epo）是一种受红细胞和中枢神经系统神经元缺氧调节的造血细胞因子，最近被证明可保护中枢神经系统神经元免于凋亡和缺血性死亡。我们最近报道了Epo在周围神经损伤部位，特别是在雪旺细胞中，在慢性收缩损伤（CCI）引起的神经病变中上调。两种神经性疼痛动物模型的初步数据支持我们的假设，即Epo通过激活神经保护信号级联来抑制疼痛行为和DRG凋亡。我们提出这些事件背后的机制包括Epo与其受体（EpoR）从神经损伤部位逆行运输到DRG，其中磷酸化的JAK2（与EpoR相关的酪氨酸激酶）激活神经保护信号。我们将通过在CCI神经病变和L5脊髓神经挤压损伤时局部注射rhEpo，并测量细胞凋亡和疼痛行为来验证这些假设。在体内和体外实验中，我们将预先给药一种干扰Epo/EpoR功能的Epo结合拮抗剂，以及一种阻止JAK2介导的信号传导的JAK2药理学抑制剂。该实验将为神经损伤和疼痛的基本机制提供新的信息，从而为开发新的神经保护策略来预防慢性神经性疼痛提供新的理论依据。网站性能 ======================================== 节结束 ===========================================

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===========================================