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，它是由各种不同的 这导致难以提供有效的信息， 治疗。慢性疼痛的一个关键机制，如伤害性疼痛，是中枢性的。 脊髓水平的可塑性变化导致并维持高度伤害感受的致敏作用。 为了增加进一步的复杂性，我们发现急性、过渡和慢性的基础机制不同 在我们的伤害性疼痛模型中的中枢致敏阶段。为了更好地理解， 成功地治疗，慢性疼痛条件，这三个阶段的机制，以及解决 慢性疼痛，必须加以阐明。我已经证明辣椒素敏感性传入神经的兴奋 减弱sGABAn对低强度突触刺激的反应。此外，我已经证明， 小胶质细胞和炎症介导了伤害性疼痛状态下的中枢致敏的慢性阶段。 在拟议项目的F99阶段，我将进一步描述神经元回路的特点。 中枢致敏的急性和维持阶段，重点是1）伤害感受器激活和随后的 在急性期，活性氧自由基的释放损害Aβ-纤维诱发的sGABAn激活，2）是否 这种损伤允许低阈值传入输入激活脊髓小胶质细胞以驱动过渡期， 以及3）反应性小胶质细胞和炎症介质是否在慢性期维持损伤。 在K 00阶段，我将转移到一个著名的疼痛研究实验室，通过以下方式研究其机制： 哪些促消退脂质介质，如消退素，在疼痛条件下失调，以及它们对 伤害感受回路此外，我将研究如何resolvins和电路，他们的影响可能是 将慢性疼痛转化为缓解疼痛 总的来说，拟议项目将提供关键的理解， 伤害性神经回路敏化这些将最终揭示新的治疗靶点， 开发更好的疼痛治疗方法。