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: 10677714
• 负责人: Lingyong Li
• 金额: $ 44.26万
• 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/10677714
• 关键词: Actins; Antisense Oligonucleotides; Brain; Clinic; Cre driver; Cytoskeletal Modeling; Dendritic Spines; Development; Diabetes Mellitus; Growth; Heterogeneity; Hypersensitivity; Inflammation; Link; LoxP-flanked allele; Mediating; Modeling; Molecular; Morphogenesis; Mus; Nature; Neurotrophic Tyrosine Kinase Receptor Type 2; Nociception; Pathologic; Peripheral; Peripheral nerve injury; Play; Polymers; Population; Posterior Horn Cells; Rattus; Research; Rodent Model; Role; Signal Pathway; Signal Transduction; Signaling Protein; Spinal; Spinal nerve structure; Synapses; Synaptic Potentials; Synaptic plasticity; Testing; Therapeutic Effect; Transgenic Organisms; Translating; Vertebral column; Viral Vector; central sensitization; chemotherapy; chronic pain; chronic pain management; chronic painful condition; density; dorsal horn; effective therapy; excitatory neuron; functional plasticity; genetic manipulation; inflammatory pain; link protein; nerve injury; neural; new therapeutic target; pain processing; painful neuropathy; polymerization; prevent; rho GTP-Binding Proteins; spared nerve; targeted treatment; therapeutic target

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.

项目摘要/摘要 这项建议的主要目标是确定作为发展基础的保守机制 评估不同类型的慢性疼痛，并确定一个易于处理的目标，对治疗具有广泛的影响。尽管差异很大 病理触发和不同的上游信号通路，伤害性活动诱导的功能性和 脊髓背角的结构可塑性是不同类型脊髓损伤的共同神经基质。 慢性疼痛。然而，目前还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是否在不同类型的 慢性疼痛。Rho GTP酶(如rac1和RhoA)在树突棘的形态发生和 通过控制肌动蛋白细胞骨架组织的突触可塑性。特别是，rac1促进了细胞的形成， 脊椎和突触的生长和稳定。我们之前发现Tiam1是rac1的关键调节因子- 脑发育中的脊椎形态发生依赖。Tiam1被突触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感化与慢性疼痛密切相关 树突棘的大小和密度的增加是由过敏性和Rac1依赖性增加引起的。 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 在神经病理性疼痛条件下，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稳定化。此外，Tiam1从兴奋性基因中缺失 神经元或脊髓背角神经元防止由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，即Tiam1链接 伤害性活动-激活NMDAR和TrkB受体对rac1信号，协调突触结构 肌动蛋白骨架重组的可塑性和突触NMDAR稳定的功能可塑性 脊髓背角内的兴奋性神经元群体，这是一种保守的机制 不同类型的慢性疼痛的发展，并可作为治疗慢性疼痛干预的靶点。我们 将追求以下三个具体目标：1)确定天津市S在不同类型慢性肾衰患者中的收敛功能 疼痛；2)阐明Tiam1对不同类型慢性疼痛的作用机制；3)验证 脊髓Tiam1作为治疗慢性疼痛的靶点。在这个项目完成后，我们将 揭示不同类型慢性疼痛形成的保守机制，并找出 新的治疗靶点，可转化为临床治疗慢性疼痛，具有广泛的意义。