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 该提案的主要目的是确定开发基础的配置机制 在不同类型的慢性疼痛中，并确定了对治疗的广泛影响的可疗法靶标。尽管潜水员 病理触发器和不同的上游信号通路，伤害性活性引起的功能和 脊髓角中的结构可塑性是不同类型的常见神经底物 慢性疼痛。但是，尚不清楚哪种分子机制协调结构和功能 脊髓角中的可塑性以及这些机制是否在不同类型的 慢性疼痛。 Rho GTPases（例如Rac1和Rhoa）在树突状脊柱形态发生和 通过控制肌动蛋白细胞骨架组织的突触可塑性。尤其是Rac1促进了形成， 刺和突触的生长和稳定。我们以前以前将TIAM1确定为Rac1-的关键调节剂 依赖性脊柱形态发生在大脑发育中。 TIAM1被突触NMDAR和TRKB激活 受体并介导了它们对肌动蛋白和脊柱重塑的影响。在疼痛处理期间，NMDAR和 TRKB受体介导的脊柱背角中的中枢灵敏度与慢性疼痛至关重要 超敏反应和Rac1依赖性树突状刺的大小和密度的增加是长期的 慢性疼痛的术语性质。我们的初步研究发现TIAM1在脊髓角中激活 在神经性疼痛条件下，通过促进周围神经损伤调制突触重塑 - 诱导肌动蛋白聚合和突触NMDAR稳定。此外，tiam1从兴奋性中删除 神经元或脊柱背角神经元可防止周围神经损伤触发的慢性疼痛发育， 化学疗法，糖尿病和炎症。在此提案中，我们将测试tiam1链接的中心假设 对Rac1信号传导的伤害活性活化的NMDAR和TRKB受体，策划合成结构 通过肌动蛋白细胞骨架重组和通过突触NMDAR稳定在功能可塑性中的可塑性 脊柱背角中的兴奋性神经元种群，它是一种保守机制 开发不同类型的慢性疼痛，可以针对治疗性慢性疼痛干预。 将追求以下三个特定目标：1）在不同类型的慢性中识别Tiam1的收敛功能 疼痛; 2）阐明TIAM1促进不同类型的慢性疼痛的机制； 3）验证 脊柱TIAM1是治疗慢性疼痛的治疗靶标。该项目完成时，我们将 发现一种构成的机制，该机制是不同类型的慢性疼痛发展的基础 可以转化为诊所的新型热靶标具有广泛的影响。