Project 3: Lei

尽管人们普遍认为，神经损伤后，伤害性感受器及其中枢中继神经元会经历 神经可塑性适应和这些变化可以显著影响慢性疼痛状态，了解 目前尚缺乏调控神经损伤后伤害性感受器可塑性的转录程序。 我们最近报道了转录因子SOXL-1调节神经母细胞瘤存活和轴突生长。 胚胎感觉神经元，包括伤害性感受器。SOXL 1是为数不多的转录因子之一，其 神经损伤后感觉神经元的表达显著上调。我们假设 神经损伤后Sox11的上调是神经系统促进的适应性变化 动态平衡和远端神经的再支配，防止神经病理性疼痛的发展。 或者，神经损伤后SOXL-1的上调可能导致伤害性反应的转录变化。 改变阈值、兴奋性和传递特性并导致疼痛的神经元 过敏症。在这项提案中，我们将使用新开发的伤害性感受器特异的Soxli CKO小鼠来 直接测试我们的假设。我们有三个具体目标：1)研究SOXL-1在调节迟滞中的作用 伤害性感受器的发育，包括存活、轴突生长和靶神经支配，以及 伤害性感受器特异性离子通道和受体；2)确定SOXL 1上调是否促进或 抑制周围神经损伤后行为过敏的发展。我们将比较 SOXL-1 CKO小鼠和对照仔鼠对机械和热刺激2周后的行为反应 神经损伤的类型，坐骨神经挤压，允许远端神经再支配，以及L5脊柱 不允许神经再支配的神经切断；以及3)评估SOXL-1在轴突生长中的作用 周围神经损伤后的靶神经再支配。我们研究的长期目标是了解 神经损伤后调控伤害性感受器可塑性的分子机制 预防和管理慢性疼痛的治疗目标。

Although it is generally accepted that after nerve injury, nociceptors and their central relay neurons undergo neuroplastic adaptations and these changes can significantly affect chronic pain status, knowledge regarding the transcription program that regulates the plasticity of nociceptors after nerve injury is currently lacking. We recently reported that the transcription factor Soxl 1 regulates the survival and axonal growth of embryonic sensory neurons including nociceptors. Soxl 1 is one of the few transcription factors whose expression is significantly upregulated in sensory neurons after nerve injury. We hypothesize that the upregulation of Sox11 after nerve injury is an adaptive change on the part of the nervous system to promote homeostasis and reinnervation of distal territories, protecting against the development of neuropathic pain. Alternatively, the upregulation of Soxl 1 after nerve injury may lead to transcriptional changes in nociceptive neurons that alter their threshold, excitability and transmission properties and contribute to pain hypersensitivity. In this proposal, we will use newly developed nociceptor-specific Soxli CKO mice to directly test our hypotheses. We have three specific aims: 1) Examine the role of Soxl 1 in regulating latestage nociceptor development including survival, axonal growth and target innervation, and expression of nociceptor-specific ion channels and receptors; 2) Determine whether the upregulation of Soxl 1 promotes or inhibits the development of behavioral hypersensitivity after peripheral nerve injury. We will compare the behavioral responses of Soxl 1 CKO mice and control littermates to mechanical and thermal stimuli after two types of nerve injuries, sciatic nerve crush which allows for reinnervation of distal territories, and L5 spinal nerve transection which does not allow for reinnervation; and 3) Assess the role of Soxl 1 in axonal growth and target reinnervation after peripheral nerve injury. The long-term goal of our study is to understand the molecular mechanisms that regulate the plasticity of nociceptors after nerve injury in order to identify novel therapeutic targets for prevention and management of chronic pain.