The Role of Cell-specific TLR-4 Signaling in Developing Chronic Pain

细胞特异性 TLR-4 信号传导在慢性疼痛发展中的作用

• 批准号: 9563328
• 负责人: Michael D Burton
• 金额: $ 22.98万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9563328
• 关键词: Ablation; Affect; Afferent Neurons; Agonist; American; Animals; Area; Automobile Driving; Biological Assay; Calcium; Cells; Data; Development; Diabetes Mellitus; Dietary Fats; Dietary Sugars; Disease; Electrophysiology (science); Eukaryotic Initiation Factors; Event; Foundations; Generations; Genetic; Genetic Models; Goals; HMGB1 gene; Heart Diseases; Image; Immune response; Incidence; Inflammation; Inflammation Mediators; Inflammatory; Injury; Knock-out; Knockout Mice; Lead; Link; Literature; LoxP-flanked allele; MAP Kinase Gene; Maintenance; Malignant Neoplasms; Mediating; Medical; Mentors; Methods; Microglia; Minor; Modeling; Molecular; Mus; Neuraxis; Neuronal Injury; Neurons; Neurosciences; Nociception; Nociceptors; Nonesterified Fatty Acids; Pain; Pathology; Pathway interactions; Patients; Pattern; Peripheral; Peripheral Nervous System; Pharmacology; Phase; Phenotype; Physiological; Play; Population; Prevention; Price; Productivity; Reporting; Research; Role; Signal Transduction; Site; Spinal Ganglia; Stroke; System; TLR4 gene; Therapeutic; Time Study; Toll-like receptors; Training; Transgenic Organisms; Translations; Traumatic Nerve Injury; career; cell type; chemotherapy; chronic neuropathic pain; chronic pain; cost; diabetic; dimorphism; experimental study; in vivo; insight; macrophage; medical attention; nerve injury; novel; novel therapeutic intervention; novel therapeutics; pain model; pain relief; painful neuropathy; patient population; public health relevance; spared nerve; theories; therapeutic target; tool; training opportunity

 DESCRIPTION (provided by applicant): More Americans are affected by pain than heart disease, stroke, and cancer combined. In particular, neuropathic pain is responsible for a large percentage of these incidences of pain. The mechanisms that underlay the development of neuropathic pain are highly sought after, because current therapeutics fails to offer relief in ove half of patients. Neuronal injury or stimulation leading to maladaptive hyperexcitability appears to play a huge role in the development of neuropathic pain and the identification of therapeutic targets that can modulate neuronal action will be important as viable treatment options. Interestingly, TLR4 has been shown to be expressed on peripheral sensory neurons, which suggests neurons are activated directly by TLR4 agonists (LPS, HMGB1, free fatty acids etc.) to play an active role in peripheral nervous system plasticity leading to neuropathic pain. This study will focus on the peripheral nervous system bringing genetic tools to clarify the functional role of DRG nociceptive neurons versus macrophage/microglia TLR4 in developing neuropathic pain. Importantly, downstream signaling events connected to TLR4 activation in neurons are largely unknown and provide an additional layer of therapeutic focus. The Price lab has generated evidence that translation control signaling mechanisms via the eukaryotic translation initiation factor-4E (eIF4E) are required for the development and maintenance of neuropathic pain; and other groups have recently shown that TLR4 may activate the MAPK pathway that modulates eIF4E. A key feature of this proposal is that we will, for the first time, study the physiological relevance of TLR4 in specific cell populations in vivo to determine whether nociceptor or macrophage/microglia TLR4 is necessary and/or sufficient for the development of neuropathic pain. We will take advantage of the cre-lox transgenic system offering cell-specific ablation or reactivation of TLR4 using newly developed floxed mice and continued development of null-reactivatable mice (Joel Elmquist). We will cross these animals with Nav1.8-cre (sensory neuron) and LysM-cre (macrophage/microglia) animals to assess these particular populations in developing neuropathic pain. Our research is aimed at understanding mechanisms driving chronic pain and moving these molecular insights toward new therapeutic strategies for pain alleviation. To accomplish these goals we propose the following specific aims: 1) Determine the role of cell-specific TLR4-eIF4E signaling to develop neuropathic pain during the mentored phase, and 2) Determine the contribution of TLR4 expression in nociceptors vs. microglia to neuropathic pain in phase II. These studies will hopefully suggest novel therapeutic avenues for the treatment and prevention of chronic pain by targeting nociceptor and microglial TLR4 signaling, translational control, and phenotype switching. Drs. Theodore Price and Joel Elmquist are ideally suited as mentors for this project with their complementary expertise in chronic pain development and mouse genetics, respectively.

 描述（由申请人提供）：受疼痛影响的美国人比心脏病、中风和癌症的总和还要多。特别是，神经性疼痛占这些疼痛发生率的很大一部分。神经性疼痛的发生机制是。受到高度追捧，因为目前的治疗方法无法缓解超过一半的患者的神经元损伤或刺激，导致适应不良的过度兴奋似乎在神经性疼痛的发展和治疗靶点的识别中发挥着巨大的作用。调节神经元作用作为可行的治疗选择是很重要的，TLR4 已被证明在外周感觉神经元上表达，这表明神经元被 TLR4 激动剂（LPS、HMGB1、游离脂肪酸等）直接激活以发挥积极作用。这项研究将重点关注周围神经系统，利用遗传工具来阐明 DRG 伤害性神经元与巨噬细胞/小胶质细胞 TLR4 在神经病理性疼痛中的功能作用。重要的是，与神经元中 TLR4 激活相关的下游信号事件在很大程度上是未知的，并且提供了额外的治疗焦点，Price 实验室已经提供了证据，表明通过真核翻译起始因子 4E (eIF4E) 的翻译控制信号机制是开发所必需的。和神经性疼痛的维持；以及其他小组最近表明 TLR4 可能激活调节 eIF4E 的 MAPK 通路，该提案的一个关键特征是我们将首次研究 TLR4 在中的生理相关性。我们将利用 cre-lox 转基因系统，使用新开发的 TLR4 进行细胞特异性消融或重新激活。 floxed 小鼠和继续开发无效可重新激活小鼠 (Joel Elmquist) 我们将这些动物与 Nav1.8-cre（感觉神经元）和LysM-cre（巨噬细胞/小胶质细胞）动物来评估这些特定人群发生神经性疼痛的情况，我们的研究旨在了解驱动慢性疼痛的机制，并将这些分子见解转向新的缓解疼痛的治疗策略。具体目标：1) 确定细胞特异性 TLR4-eIF4E 信号传导在指导阶段产生神经性疼痛的作用，2) 确定 TLR4 表达在伤害感受器与非伤害性感受器中的贡献。这些研究有望通过针对伤害感受器和小胶质细胞 TLR4 信号传导、翻译控制和表型转换来提供治疗和预防慢性疼痛的新方法。该项目的导师分别在慢性疼痛发展和小鼠遗传学方面具有互补的专业知识。