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.

项目总结/摘要 该建议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，并确定一个易于处理的目标与治疗的广泛影响。尽管多样 病理触发和不同的上游信号传导途径，伤害性活动诱导的功能和 脊髓背角的结构可塑性是不同类型的脊髓损伤的共同神经基质。 慢性疼痛然而，目前还不清楚是哪些分子机制协调了结构和功能， 脊髓背角的可塑性，以及这些机制是否在不同类型的脊髓背角中保持不变。 慢性疼痛Rho GTP酶（例如，Rac 1和RhoA）在树突棘形态发生中起重要作用， 突触可塑性通过控制肌动蛋白细胞骨架组织。特别地，Rac 1促进了 生长和稳定的棘和突触。我们以前确定Tiam 1是Rac 1的关键调节因子， 脑发育中的脊椎形态发生。Tiam 1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化与慢性疼痛密切相关 超敏反应和Rac 1依赖性树突棘的大小和密度增加解释了长- 长期慢性疼痛的性质。我们的初步研究发现Tiam 1在脊髓背角被激活， 在神经病理性疼痛条件下，通过促进外周神经损伤调节突触重塑- 诱导肌动蛋白聚合和突触NMDAR稳定。此外，Tiam 1从兴奋性 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本提案中，我们将测试我们的中心假设，即Tiam 1连接 伤害感受活性激活NMDAR和TrkB受体对Rac 1信号传导，协调突触结构 通过肌动蛋白细胞骨架重组的可塑性和通过突触NMDAR稳定的功能可塑性， 兴奋性神经元群体在脊髓背角，这是一个保守的机制， 该方法可以预防不同类型的慢性疼痛的发展，并且可以针对治疗性慢性疼痛干预。我们 我们将致力于以下三个具体目标：1）确定Tiam 1在不同类型慢性疾病中的会聚功能。 疼痛; 2）阐明Tiam 1导致不同类型慢性疼痛的机制; 3） 脊髓Tiam 1作为治疗慢性疼痛的治疗靶点。在这个项目完成后，我们将 揭示一种保守的机制，这种机制是不同类型慢性疼痛发展的基础，并确定一种 新的治疗靶点，可以转化为临床治疗慢性疼痛具有广泛的意义。