The conserved mechanisms underlying different types of chronic pain

不同类型慢性疼痛的保守机制

• 批准号: 10747177
• 负责人: Lingyong Li
• 金额: $ 44.96万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747177
• 关键词: conserved; mechanisms; underlying; different; types

PROJECT SUMMARY/ABSTRACT The primary objective of this proposal is to determine the conserved mechanism that underlies the development of different types of chronic pain and identify a tractable target with broad implications for therapy. Despite diverse pathological triggers and different upstream signaling pathways, nociceptive activity-induced functional and structural plasticity in the spinal dorsal horn serves as the common neural substrate for the different types of chronic pain. However, it remains unclear which molecular mechanisms orchestrate structural and functional plasticity in the spinal dorsal horn and whether these mechanisms are conserved across the different types of chronic pain. Rho GTPases (e.g., Rac1 and RhoA) play essential roles in dendritic spine morphogenesis and synaptic plasticity by controlling actin cytoskeleton organization. In particular, Rac1 promotes the formation, growth, and stabilization of spines and synapses. We previously identified Tiam1 as a critical regulator of Rac1- dependent spine morphogenesis in brain development. Tiam1 is activated by synaptic NMDARs and TrkB receptors and mediates their effects on actin and spine remodeling. During the pain processing, NMDARs and TrkB receptors-mediated central sensitization in the spinal dorsal horn are critically involved in chronic pain hypersensitivity, and Rac1-dependent increases in the size and density of dendritic spines account for the long- term nature of chronic pain. Our preliminary studies found that Tiam1 was activated in the spinal dorsal horn under neuropathic pain conditions and modulated synaptic remodeling by promoting peripheral nerve injury- induced actin polymerization and synaptic NMDAR stabilization. Moreover, Tiam1 deletion from excitatory neurons or spinal dorsal horn neurons prevented chronic pain development triggered by peripheral nerve injury, chemotherapy, diabetes, and inflammation. In this proposal, we will test our central hypothesis that Tiam1 links nociceptive activity-activated NMDARs and TrkB receptors to Rac1 signaling, orchestrating synaptic structural plasticity via actin cytoskeleton reorganization and functional plasticity via synaptic NMDAR stabilization in excitatory neuron populations in the spinal dorsal horn, which serves as a conserved mechanism underlying the development of different types of chronic pain and can be targeted for therapeutic chronic pain intervention. We will pursue the following three specific aims: 1) Identify Tiam1’s convergent function in different types of chronic pain; 2) Elucidate the mechanisms by which Tiam1 contributes to different types of chronic pain; 3) Validate spinal Tiam1 as a therapeutic target for the treatment of chronic pain. At the completion of this project, we will uncover a conserved mechanism that underlies the development of different types of chronic pain and identify a novel therapeutic target that could be translated into the clinic to treat chronic pain with broad implications.

项目概要/摘要 该提案的主要目标是确定发展背后的保守机制 不同类型的慢性疼痛，并确定对治疗具有广泛影响的可处理目标。尽管多种多样 病理触发因素和不同的上游信号通路、伤害感受活动诱导的功能和 脊髓背角的结构可塑性是不同类型神经元的共同神经基质 慢性疼痛。然而，目前尚不清楚哪些分子机制协调结构和功能 脊髓背角的可塑性以及这些机制在不同类型的动物中是否保守 慢性疼痛。 Rho GTPases（例如 Rac1 和 RhoA）在树突棘形态发生和 通过控制肌动蛋白细胞骨架组织来实现突触可塑性。特别是，Rac1 促进形成， 棘和突触的生长和稳定。我们之前确定 Tiam1 是 Rac1 的关键调节因子 大脑发育中依赖的脊柱形态发生。 Tiam1 由突触 NMDAR 和 TrkB 激活 受体并介导其对肌动蛋白和脊柱重塑的影响。在疼痛处理过程中，NMDAR 和 TrkB 受体介导的脊髓背角中枢敏化与慢性疼痛密切相关 超敏反应以及 Rac1 依赖性树突棘大小和密度的增加是长期 慢性疼痛的术语性质。我们的初步研究发现Tiam1在脊髓背角被激活 在神经性疼痛条件下并通过促进周围神经损伤来调节突触重塑- 诱导肌动蛋白聚合和突触 NMDAR 稳定。此外，Tiam1从兴奋性中缺失 神经元或脊髓背角神经元可防止周围神经损伤引发的慢性疼痛发展， 化疗、糖尿病和炎症。在这个提案中，我们将测试我们的中心假设：Tiam1 链接 伤害感受活性激活 NMDAR 和 TrkB 受体至 Rac1 信号传导，协调突触结构 通过肌动蛋白细胞骨架重组实现可塑性，通过突触 NMDAR 稳定实现功能可塑性 脊髓背角的兴奋性神经元群，这是脊髓背角的保守机制 不同类型慢性疼痛的发展，可以作为治疗性慢性疼痛干预的目标。我们 将追求以下三个具体目标：1）确定Tiam1在不同类型慢性疾病中的收敛功能 疼痛; 2) 阐明Tiam1导致不同类型慢性疼痛的机制； 3）验证 脊髓 Tiam1 作为治疗慢性疼痛的治疗靶点。在这个项目完成后，我们将 揭示不同类型慢性疼痛发展背后的保守机制，并确定 可以转化为临床治疗慢性疼痛的新治疗靶点，具有广泛的意义。