Role of Piezo1 in Mechanical Touch and Nociception

Piezo1 在机械触摸和伤害感受中的作用

• 批准号: 10536601
• 负责人: Vanessa Ehlers
• 金额: $ 6.95万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10536601
• 关键词: Action Potentials; Afferent Neurons; Agonist; Animals; Attention; Behavioral; Behavioral Assay; Cations; Cells; Characteristics; Cutaneous; Data; Detection; Development; Electrophysiology (science); Esthesia; Fiber; Freund' s Adjuvant; Goals; Homologous Gene; Human; Hyperalgesia; Hypersensitivity; Inflammation; Injury; Ion Channel; Ion Channel Gating; Measures; Mechanical Stimulation; Mechanics; Mechanoreceptors; Mediating; Mus; Nature; Nerve; Neurons; Nociception; Organism; Pain; Pain management; Pathologic; Peripheral; Peripheral Nerves; Peripheral Nervous System; Peripheral Nervous System Diseases; Peripheral nerve injury; Persistent pain; Piezo 1 ion channel; Piezo 2 ion channel; Play; Prevalence; Proprioception; Reporting; Rodent; Role; Skin; Spinal Ganglia; Stimulus; Structure of tibial nerve; System; Tactile; Testing; Tissues; Touch sensation; Transcript; Transgenic Mice; Traumatic Nerve Injury; Wild Type Mouse; Work; cellular targeting; comparative; experimental study; inflammatory pain; keratinocyte; mechanical allodynia; mechanical force; mechanical stimulus; mechanotransduction; nerve injury; overexpression; pain sensation; painful neuropathy; patch clamp; peripheral pain; pharmacologic; release of sequestered calcium ion into cytoplasm; response; severe injury; single-cell RNA sequencing; somatosensory; spared nerve; translational potential; transmission process

PROJECT SUMMARY Detection of mechanical stimuli is crucial for organisms' development and survival. Discriminating between an innocuous mechanical stimulus and noxious mechanical force is vital to avoid tissue damage and resulting pain. Cutaneous mechanisms of mechanical stimulus detection have received considerable attention, however, the sensory neuron-specific mechanoreceptors underlying touch and pain are not fully understood. Piezo1 and Piezo2 ion channels are bona fide mechanotransduction cation channels expressed at various levels and tissues that comprise the peripheral nervous system, including keratinocytes and sensory neurons. While sensory neuron expression of Piezo2 is essential for peripheral sensation of tactile stimuli, relatively little is known about the role of its close relative, Piezo1. Despite early work suggesting dorsal root ganglia (DRG) sensory neurons display relatively robust Piezo2 expression and comparatively minimal Piezo1 expression, more recent evidence suggests that Piezo1 is expressed by sensory neurons and it can be mechanically and pharmacologically activated in these neurons. This suggests sensory neuron Piezo1 may be functionally important for detection of tactile and mechanical pain by the somatosensory system. Furthermore, while sensory neuron Piezo2 is implicated in mechanical allodynia, nothing is currently known about the contribution of sensory neuron Piezo1 to the mechanical allodynia or hyperalgesia characteristic of neuropathic or inflammatory pain conditions. In the experiments outlined in the current proposal, I will use evoked behavioral assays, patch clamp electrophysiology, and ex vivo skin-nerve recordings to determine the role Piezo1 plays in sensory neuron-mediated mechanosensation in naïve (non-injury) and pain (injury) contexts by using transgenic mice with sensory neuron specific deletion of Piezo1. In Aim 1, I will examine the contribution of sensory neuron-specific Piezo1 to mechanosensation (Aim 1A), to mechanically-evoked peripheral fiber responses (Aim 1B), and to DRG responses to mechanical stimuli (Aim 1C). Similar approaches will be used in Aim 2 to interrogate the role of Piezo1 in mechanical hypersensitivity induced by inflammation, using complete Freund's adjuvant, and peripheral neuropathy induced by spared tibial nerve injury. I will determine whether Piezo1 contributes to injury- induced mechanical allodynia and hyperalgesia (Aim 2A), and mechanical stimulus-induced sensitization of peripheral fibers (Aim 2B) and DRG sensory neurons (Aim 3C). These studies will ultimately reveal additional roles for mechanically-gated channels in tactile stimulus transduction. Overall, the proposed aims will reveal the contribution of sensory neuron Piezo1 to detection of mechanical stimuli in non-injury and injury conditions, potentially revealing new avenues for treatment of mechanical pain.

项目摘要 机械刺激的检测对于生物的发育和生存至关重要。区分一个 无害的机械刺激和有害的机械力对于避免组织损伤和导致疼痛至关重要。 机械刺激检测的皮肤机制已受到了考虑的关注，但是， 触摸和疼痛的感官神经特异性机制感受器尚不完全了解。压电和 压电2离子通道是在各个级别和组织中表达的善意机械传输阳离子通道 其中包括外周神经系统，包括角质形成细胞和感觉神经元。而感官 压电2的神经元表达对于触觉刺激的周围感觉是必不可少的，对 其亲戚的作用Piezo1。尽管早期工作暗示背根神经节（DRG）感觉神经元 显示相对强大的压电2表达和相对最小的压电表达，最近的证据 表明Piezo1由感觉神经元表达，并且可以在机械上和药物上进行 在这些神经元中激活。这表明感觉神经元压电1对于检测的功能可能很重要 体感系统的触觉和机械疼痛。此外，感觉神经元压电是 在机械性异常尼亚实施，目前对感觉神经元压电的贡献一无所知 神经性或炎症性疼痛状况的机械性异常性症或痛觉过敏。在 当前提案中概述的实验，我将使用诱发的行为测定，斑块夹电生理学， 并在体内皮肤上的记录，以确定在感觉神经元介导的作用Piezo1扮演的作用 通过使用感官神经元的转基因小鼠，幼稚（非伤害）和疼痛（损伤）的机械密度 压电1的特定缺失。在AIM 1中，我将研究感觉神经元特异性压电对 机理（AIM 1A），用于机械诱发的外围纤维响应（AIM 1B）和DRG 对机械刺激的反应（AIM 1C）。 AIM 2将使用类似的方法来审问 通过炎症引起的机械性超敏反应，使用完整的Freund的调整和 由幸免的胫骨神经损伤引起的周围神经病。我将确定压电1是否有助于伤害 - 诱导的机械性异常和痛觉过敏（AIM 2A），以及机械刺激诱导的灵敏度 周围纤维（AIM 2B）和DRG感觉神经元（AIM 3C）。这些研究最终将揭示更多 机械门控通道在触觉刺激翻译中的作用。总体而言，拟议的目标将揭示 感觉神经元压电1对在不伤人和损伤条件下检测机械刺激的贡献， 有可能揭示用于治疗机械疼痛的新途径。