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: 10543744
• 负责人: Tyler B. Waltz
• 金额: $ 3.41万
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543744
• 关键词: ANK1 gene; Action Potentials; Afferent Neurons; Age; Agonist; Analgesics; Axon; Behavioral; Biological Assay; Calcium; Cell membrane; Cells; Chemicals; Chronic; Circulation; Clinical; Clinical Trials; Data; Disease; Electrophysiology (science); Exhibits; Fabry Disease; Face; Fiber; Foundations; Genes; Genetic; Hydrogen Peroxide; Hypersensitivity; Image; Inflammatory; Injury; Ion Channel; Learning; Link; Lipids; Literature; Lysosomal Storage Diseases; Mechanical Stimulation; Mechanics; Mediating; Mediator; Meditation; Methods; Modeling; Morphology; Nerve; Nerve Fibers; Neural Conduction; Neuroglia; Neurons; Neurosciences Research; Nociceptors; Pain; Pain management; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Persistent pain; Phenotype; Play; Property; Rattus; Recommendation; Role; Schwann Cells; Sensory; Signal Transduction; Skin; Spinal Ganglia; Stimulus; TRP channel; Techniques; Transgenic Organisms; Viral; afferent nerve; chronic pain; conditioned place preference; effective therapy; experience; extracellular; globotriaosylceramide; inhibitor; knock-down; mechanical drive; mechanical force; pain behavior; patch clamp; peripheral nerve damage; pharmacologic; 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.

项目摘要 法布里病（FD）是最常见的溶酶体储存疾病之一，会导致毁灭性的疼痛 从小就开始的患者。虽然临床文献表明，FD患者具有机械的 诱发的疼痛，持续的疼痛和周围神经损伤，目前尚不清楚FD疼痛如何介导 周围神经系统（PNS）。我的建议将研究PNS细胞机制如何介导FD疼痛 使用FD大鼠模型，该模型概括了患者中看到的疼痛表型。异常离子通道 神经元的活性与许多疾病中周围介导的疼痛有关。但是，最近的证据有 表明神经元中的疼痛相关离子通道也在非神经元细胞中表达。减少 Schwann细胞（SC）离子通道活性可以在其他疼痛中改善机械诱发的疼痛 状况。已经假设从SC释放的算法正在影响机械诱发 疼痛。我们已经表明，FD中的机械诱发的疼痛取决于离子通道瞬态的活性 PNS中的受体电势arnkyrin 1（TRPA1）。在我的建议中，我将确定TRPA1是否也进行了调解 FD大鼠的PNS活性持续疼痛。我还将确定算法是否从FD SCS释放 或使神经元对机械力敏感，如果SC TRPA1在FD中驱动机械诱发的疼痛。我 假设TRPA1在Schwann细胞和神经元中的活性增加至关重要 在FD大鼠中维持慢性疼痛表型。在AIM 1中，我将确定FD大鼠是否具有行为 持续的疼痛和异常的周围神经活性取决于TRPA1。我将使用一台正在进行的电池 疼痛行为技术并确定TRPA1抑制是否减轻了这种疼痛（AIM 1A）。然后我会确定 是否需要使用Ex Vivo嘲笑FD大鼠的自发轴突活性需要外围TRPA1 纤维记录（AIM 1B）。在AIM 2中，我将研究SC在TRPA1依赖机械中扮演的角色 Fd中的高敏性。首先，我将确定感官神经元是否被算法激活或敏感 从FD SCS释放，如果此激活需要神经元TRPA1（AIM 2A）。接下来，我将确定是否 FD SCS的算法将神经元敏感到使用贴片钳记录的机械刺激，如果此，则 取决于神经元TRPA1活性（AIM 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分析来减轻FD机械性超敏反应（AIM 2C）。我的建议会 提供了雪旺细胞如何介导慢性疼痛的基础，并将提高我们对 法布里病疼痛。