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）是最常见的溶酶体贮积病之一，并导致严重的疼痛。 患者开始在年轻的时候。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。 外周神经系统（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，其概括了在患者中观察到的疼痛表型。异常离子通道 在许多疾病中，神经元上的活动与外周介导的疼痛有关。然而，最近的证据表明， 显示神经元中的疼痛相关离子通道也在非神经元细胞中表达。降低 雪旺细胞（SC）离子通道活性可以在行为上改善机械诱发的疼痛 条件已经假设从SC释放的致藻原影响机械诱发的 痛苦我们已经证明FD中机械诱发的疼痛依赖于离子通道瞬变的活性， PNS中的受体电位锚蛋白1（TRPA 1）。在我的建议中，我将确定TRPA 1是否也介导 持续疼痛通过PNS活性的FD大鼠。我还将确定FD SC释放的致敏原是否被激活 或使神经元对机械力敏感，以及SC TRPA 1是否驱动FD中的机械诱发疼痛。我 假设雪旺细胞和神经元中TRPA 1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大鼠是否具有行为 持续的疼痛和依赖于TRPA 1的异常外周神经活动。我将使用一组正在进行的 疼痛行为技术并确定TRPA 1抑制是否缓解了这种疼痛（目标1A）。然后我会决定 外周TRPA 1是否是FD大鼠自发轴突活动所必需的， 纤维记录（Aim 1B）。在目标2中，我将研究SC在TRPA 1依赖性机械性细胞凋亡中的作用。 FD中的超敏反应。首先，我将确定感觉神经元是否被致痛原激活或致敏 从FD SC释放，以及是否需要神经元TRPA 1进行这种激活（目的2A）。接下来，我将确定 来自FD SC的藻酸原使用膜片钳记录使神经元对机械刺激敏感，并且如果这 依赖于神经元TRPA 1活性（Aim 2B）。最后，我将确定SC TRPA 1的病毒抑制是否可以 通过一系列疼痛行为测定减轻FD机械超敏反应（Aim 2C）。我的提议将 为雪旺细胞如何介导慢性疼痛提供了基础，并将促进我们对 法布里病疼痛。