Peripheral Neuronal and Non-neuronal Mechanisms of Fabry Disease Pain

法布里病疼痛的周围神经元和非神经元机制

• 批准号: 10387377
• 负责人: Tyler B. Waltz
• 金额: $ 4.68万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10387377
• 关键词: ANK1 gene; Action Potentials; Afferent Neurons; Age; Agonist; Analgesics; Axon; Behavioral; Biological Assay; Blood Circulation; Calcium; Cells; Chemicals; Chronic; Clinical; Clinical Trials; Data; Disease; Electrophysiology (science); Exhibits; Fabry Disease; Face; Fiber; Foundations; Genes; Genetic; Hydrogen Peroxide; Hypersensitivity; Image; Inflammatory; Injury; Ion Channel; Learning; Life Experience; Link; Lipids; Literature; Lysosomal Storage Diseases; Mechanical Stimulation; Mechanics; Mediating; Mediator of activation protein; Methods; Modeling; Morphology; Nerve; Nerve Fibers; Neural Conduction; Neuroglia; Neurons; Neurosciences Research; Nociceptors; Pain; Pain management; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System; Persistent pain; Pharmacology; Phenotype; Plasma; Play; Rattus; Research; Role; Schwann Cells; Sensory; Signal Transduction; Skin; Spinal Ganglia; Stimulus; TRP channel; Techniques; Transgenic Organisms; Viral; afferent nerve; axon injury; chronic pain; conditioned place preference; effective therapy; experience; extracellular; globotriaosylceramide; inhibitor; knock-down; mechanical drive; mechanical force; pain behavior; patch clamp; peripheral nerve damage; pre-clinical; receptor; recruit; release factor; side effect; skills; spontaneous pain

PROJECT SUMMARY Fabry Disease (FD) is one of the most common lysosomal storage diseases and causes devastating pain in patients starting at a young age. While clinical literature has shown that patients with FD have mechanically- evoked pain, ongoing pain, and peripheral nerve damage, it is unclear how FD pain is mediated in the peripheral nervous system (PNS). My proposal will investigate how PNS cellular mechanisms mediate FD pain using the FD rat model, which recapitulates the pain phenotypes seen in patients. Abnormal ion channel activity on neurons is linked to peripherally mediated pain in many diseases. However, recent evidence has shown that pain-associated ion channels in neurons are also expressed in non-neuronal cells. Decreasing Schwann cell (SC) ion channel activity can ameliorate mechanically-evoked pain behaviorally in other pain conditions. It has been hypothesized that algogens released from SCs are influencing mechanically-evoked pain. We have shown that mechanically-evoked pain in FD depends on the activity of the ion channel Transient Receptor Potential Ankyrin 1 (TRPA1) in the PNS. In my proposal, I will determine if TRPA1 also mediates ongoing pain through PNS activity of FD rats. I will also determine if algogens released from FD SCs activate or sensitize neurons to mechanical force, and if SC TRPA1 drives mechanically-evoked pain in FD. I hypothesize that increased activity of TRPA1 in both Schwann cells and neurons is critical for maintaining chronic pain phenotypes in the FD rat. In Aim 1, I will determine if the FD rat has behavioral ongoing pain and aberrant peripheral nerve activity that is dependent on TRPA1. I will use a battery of ongoing pain behavior techniques and determine if TRPA1 inhibition alleviates this pain (Aim 1A). I will then determine whether peripheral TRPA1 is required for spontaneous axonal activity in the FD rat by using ex vivo teased fiber recordings (Aim 1B). In Aim 2, I will investigate the role that SCs play in TRPA1-dependent mechanical hypersensitivity in FD. First, I will determine if sensory neurons are activated or sensitized by algogens released from FD SCs, and if neuronal TRPA1 is required for this activation (Aim 2A). Next, I will determine if algogens from FD SCs sensitize neurons to mechanical stimulation using patch-clamp recordings, and if this depends on neuronal TRPA1 activity (Aim 2B). Finally, I will determine if viral inhibition of SC TRPA1 can alleviate FD mechanical hypersensitivity through a battery of pain behavior assays (Aim 2C). My proposal will provide a basis for how Schwann cells mediate chronic pain and will advance our understanding of Fabry Disease pain.

项目概要 法布里病 (FD) 是最常见的溶酶体贮积病之一，会导致严重的疼痛。 患者从年轻时就开始。虽然临床文献表明 FD 患者具有机械- 诱发性疼痛、持续性疼痛和周围神经损伤，目前尚不清楚 FD 疼痛是如何在神经系统中介导的 周围神经系统（PNS）。我的提案将研究 PNS 细胞机制如何介导 FD 疼痛 使用 FD 大鼠模型，该模型概括了患者所见的疼痛表型。离子通道异常 神经元的活动与许多疾病中外周介导的疼痛有关。然而，最近的证据表明 研究表明，神经元中与疼痛相关的离子通道也在非神经元细胞中表达。减少 施万细胞（SC）离子通道活性可以改善其他疼痛中机械诱发的疼痛 状况。据推测，SC 释放的藻原正在影响机械诱发的 疼痛。我们已经证明 FD 中机械诱发的疼痛取决于离子通道的活动 PNS 中的受体电位锚蛋白 1 (TRPA1)。在我的提案中，我将确定 TRPA1 是否也起到中介作用 通过 FD 大鼠的三七总皂苷 (PNS) 活动产生持续的疼痛。我还将确定 FD SC 释放的藻原是否会激活 或者使神经元对机械力敏感，如果 SC TRPA1 驱动 FD 中机械诱发的疼痛。我 假设雪旺细胞和神经元中 TRPA1 活性的增加对于 维持 FD 大鼠的慢性疼痛表型。在目标 1 中，我将确定 FD 大鼠是否有行为 持续疼痛和依赖 TRPA1 的异常周围神经活动。我将使用持续不断的电池 疼痛行为技术并确定 TRPA1 抑制是否可以减轻这种疼痛（目标 1A）。然后我会确定 外周 TRPA1 是否是 FD 大鼠自发轴突活动所必需的 光纤录音（目标 1B）。在目标 2 中，我将研究 SC 在 TRPA1 依赖性机械作用中发挥的作用 FD 中的超敏反应。首先，我将确定感觉神经元是否被藻原激活或敏化 从 FD SC 释放，并且该激活是否需要神经元 TRPA1（目标 2A）。接下来，我将确定是否 FD SC 中的藻原通过膜片钳记录使神经元对机械刺激敏感，如果这 取决于神经元 TRPA1 活性（目标 2B）。最后，我将确定 SC TRPA1 的病毒抑制是否可以 通过一系列疼痛行为测定减轻 FD 机械过敏（目标 2C）。我的建议将 为雪旺细胞如何介导慢性疼痛提供基础，并将增进我们对以下疾病的理解： 法布里病疼痛。