Effects of macrophage-derived exosomes on dorsal root ganglion neurons in models of systemic pain

巨噬细胞源性外泌体对全身疼痛模型中背根神经节神经元的影响

• 批准号: 10663694
• 负责人: Kathleen Erin McDonough
• 金额: $ 7.34万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663694
• 关键词: Acute; Adult; Affect; Amyloid beta-Protein; Animal Model; Area; Attenuated; Back; Brain-Derived Neurotrophic Factor; Capsaicin; Chronic; Chronic Phase; Data; Development; Electrophysiology (science); Family; Female; Fiber; Goals; Impairment; Inflammation; Inflammation Mediators; Injury; Interneuron function; Interneurons; Knowledge; Laboratory Research; Lipids; Macrophage; Maintenance; Mass Spectrum Analysis; Mediating; Microglia; Modeling; Molecular; Neuroglia; Neurons; Nociception; Nociceptors; Pain; Pain Research; Pain management; Pathway interactions; Peripheral; Phase; Phase Transition; Population; Postdoctoral Fellow; Prevention; Reactive Oxygen Species; Refractory; Research; Research Project Grants; Resolution; Role; Signal Pathway; Site; Spinal; Spinal Cord; Spinal Ganglia; Spinal cord posterior horn; Synapses; Syndrome; Techniques; United States; Vertebral column; Work; central sensitization; chronic back pain; chronic pain; chronic pain management; chronic painful condition; control theory; effective therapy; exosome; glial activation; healing; injured; insight; interest; lipid mediator; male; mouse model; neural circuit; neuronal circuitry; new therapeutic target; novel; pain chronification; pain model; painful neuropathy; response; sensory input; sexual dimorphism; skills

PROJECT SUMMARY Chronic pain is a serious condition which is produced and maintained by a variety of different mechanisms, many of which remain poorly understood This has led to difficulties in providing effective treatments. One key mechanism underlying chronic pain conditions, such as nociplastic pain, is central sensitization in which plastic changes at the level of the spinal cord contribute to and maintain hypernociception. To add further complexity, we have found that different mechanisms underlie the acute, transition, and chronic phases of central sensitization in our model of nociplastic pain. In order to better understand, and therefore successfully treat, chronic pain conditions, the mechanisms underlying these three phases, as well as resolution of chronic pain, must be elucidated. Already, I have shown that excitation of capsaicin-sensitive afferents attenuates the response of sGABAn to low-intensity synaptic stimulation. Furthermore, I have shown that spinal microglia and inflammation mediate the chronic phase of central sensitization underlying a nociplastic pain state. In the F99 phase of the proposed project, I will further characterize the neuronal circuitry underlying the acute and maintenance phases of central sensitization, focusing on 1) how nociceptor activation and subsequent release of reactive oxygen species impair Aβ-fiber-evoked sGABAn activation in the acute phase, 2) whether such impairment allows low-threshold afferent inputs to activate spinal microglia to drive the transition phase, and 3) if reactive microglia and inflammatory mediators maintain the impairment in the chronic phase. In the K00 phase, I will move to a prominent pain research laboratory to investigate the mechanisms by which pro-resolution lipid mediators, such as resolvins, are dysregulated in pain conditions, and their effect on nociceptive circuitry. Additionally, I will investigate how resolvins and the circuitry which they effect may be manipulated to convert chronic pain back to resolving pain. Overall, the proposed project will provide key understanding of the chronification and resolution of nociceptive neural circuit sensitization. These will ultimately reveal new therapeutic targets, allowing for the development of better pain treatments.

项目摘要 慢性疼痛是一种严重的疾病，由多种不同的不同 机制（其中许多机制仍然不太了解这）导致难以提供有效性 治疗。慢性疼痛状况（例如Nociplastic Pain）的一种关键机制是中心 塑料在脊髓水平上发生变化的敏化作用会导致并维持超量摄影。 为了增加进一步的复杂性，我们发现急性，过渡和慢性的不同机制是 在我们的鼻痛模型中，中央灵敏度的阶段。为了更好地理解，因此 成功治疗，慢性疼痛状况，这三个阶段的基础机制以及解决方案 必须阐明慢性疼痛。我已经证明了对辣椒素敏感的传入的兴奋 减弱了sgaban对低强度突触刺激的反应。此外，我已经证明了脊柱 小胶质细胞和感染介导了单张教疼痛状态的基础中心灵敏度的慢性阶段。 在拟议项目的F99阶段，我将进一步表征下面的神经元电路 中央灵敏度的急性和维护阶段，重点是1）伤害感受器如何激活和随后的激活 活性氧的释放损害了急性期Aβ纤维诱发的sgaban激活，2）是否是否 这种障碍使低阈值传入输入能够激活脊柱小胶质细胞以驱动过渡阶段， 3）如果反应性小胶质细胞和炎症介质在慢性期保持损害。 在K00阶段，我将转到一个突出的疼痛研究实验室，以研究 在疼痛条件下，哪些促分辨率脂质介质（例如分解子）失调，它们对 伤害性电路。此外，我将调查分辨率如何及其影响的电路 操纵以将慢性疼痛转化为解决疼痛。 总体而言，拟议的项目将提供对编织和分辨率的关键理解 伤害性神经电路传感器。这些最终将揭示新的治疗靶点，从而允许 发展更好的疼痛治疗。