Project 3: Lei

项目3：雷

• 批准号: 8689117
• 负责人: Lei Lei
• 金额: $ 22.07万
• 依托单位: UNIVERSITY OF NEW ENGLAND
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8689117
• 关键词: Action Potentials; Adult; Adverse effects; Affect; Affective; Afferent Neurons; Analgesics; Axon; Behavioral; Binding; Boxing; Cell Death; Cells; Cerebral cortex; Chemicals; Cholera Toxin; Cutaneous; Defect; Development; Dextrans; Distal; Embryo; Family; Fiber; Fluorescence; Gene Targeting; Genetic Recombination; Genetic Transcription; Goals; Green Fluorescent Proteins; Homeostasis; Hypersensitivity; In Vitro; Inflammation; Injury; Instruction; Ion Channel; Knock-out; Knockout Mice; Knowledge; Label; Laboratories; Lead; Measures; Mechanics; Mediating; Membrane; Modeling; Molecular; Mus; Natural regeneration; Nerve; Nerve Crush; Nervous System Part; Neuraxis; Neurons; Nociception; Nociceptors; Pain; Pattern; Peripheral; Peripheral Nerves; Peripheral nerve injury; Prevention; Process; Property; RNA Interference; Reporter; Reporting; Role; Sensory; Site; Spinal; Spinal Ganglia; Spinal nerve structure; Staging; Stimulus; Structure of trigeminal ganglion; System; Testing; Therapeutic; Tissues; Tracer; Up-Regulation; axon growth; axon regeneration; base; chronic pain; dextran; in vivo regeneration; member; nerve injury; nerve supply; neuronal cell body; new therapeutic target; painful neuropathy; prevent; programs; receptor; recombinase; reinnervation; response; sciatic nerve; sensory stimulus; tau Proteins; transcription factor; transmission process; uptake

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.

虽然一般认为神经损伤后，伤害感受器和它们的中枢中继神经元经历 神经可塑性适应，这些变化可以显着影响慢性疼痛状态，知识， 目前缺乏调节神经损伤后伤害感受器可塑性的转录程序。 我们最近报道了转录因子Soxl 1调节神经细胞的存活和轴突生长， 包括伤害感受器的胚胎感觉神经元。Soxl 1是少数几种转录因子之一， 在神经损伤后感觉神经元中表达显著上调。我们假设 神经损伤后Sox 11的上调是神经系统的一种适应性变化， 内稳态和远端区域的神经再支配，防止神经性疼痛的发展。 或者，神经损伤后Soxl 1的上调可能导致伤害性感受神经元的转录变化。 改变其阈值、兴奋性和传递特性并导致疼痛的神经元 超敏反应在这项提议中，我们将使用新开发的伤害感受器特异性Soxli CKO小鼠， 直接检验我们的假设我们有三个具体的目标：1）研究Soxl 1在调节晚期 伤害感受器发育，包括存活、轴突生长和靶神经支配，以及 伤害感受器特异性离子通道和受体; 2）确定Soxl 1的上调是否促进或 抑制周围神经损伤后行为超敏反应的发展。我们将比较 在两次注射后，Soxl 1 CKO小鼠和对照同窝仔对机械和热刺激的行为反应 神经损伤类型，坐骨神经挤压，允许远端区域的神经再支配，以及L5脊髓 不允许神经再支配的神经横断;和3）评估Soxl 1在轴突生长中的作用 和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 调节神经损伤后伤害感受器可塑性的分子机制，以确定新的 用于预防和管理慢性疼痛的治疗靶点。