CELLULAR AND ION CHANNEL MECHANISMS UNDERLYING THE SENSE OF LIGHT TOUCH IN MAMMAL

摘要：检测轻微机械刺激或触摸的触觉敏感度在生活中至关重要，但 在病理条件下可能会受到损害，导致触觉敏感度(麻木)的降低/丧失。 麻木是化疗所致周围神经病(CIPN)最早和最常见的症状 这对癌症患者的生活质量产生了负面影响，也是化疗剂量的限制因素。 CIPN麻木的治疗方法很差，其潜在机制尚不清楚。这种对知识的缺乏 防止发展麻木CIPN的有效管理。♦A默克尔圆盘是触觉的一种主要类型 末端器官位于全身的触摸敏感点，但最丰富的是人类的指尖和 所有非灵长类哺乳动物的毛囊上都有胡须。默克尔视盘由默克尔细胞和Aβ传入神经元组成 末端形成突触样结构。我们和其他人最近发现，对默克尔的触觉刺激 在默克尔细胞中，椎间盘主要由Piezo2通道传递，Piezo2通道驱动大多数Aβ传入冲动和 行为触觉反应。最近，我们进一步发现默克尔在胡须毛囊中存在圆盘 是5-羟色胺能突触，默克尔细胞对触觉刺激的反应是释放5-羟色胺 随后驱动Aβ-传入冲动和行为触觉反应。♦在此续订申请中，我们的 新的焦点是研究默克尔椎间盘的触觉敏感性是如何调节的，以及触觉敏感性是否 可被化疗药物削弱，以解释CINP的麻木方面。我们建议使用♦ 为解决这些问题而准备的胡须毛囊有3个具体目标：目标1)阐明 默克尔盘状触觉敏感度调制的潜在机制。这一目标将集中在是否 5-羟色胺转运体在调节Merkel间盘5-羟色胺能传递中的关键作用 触觉敏感度。目的2：确定化疗药物是否以及如何损害默克尔的盘状触觉 敏感度。目的是测量5-羟色胺能传递和默克尔盘触觉敏感度的变化 在化疗药物治疗后，并识别默克尔椎间盘中突触前和突触后的分子 化疗药物靶向导致默克尔盘触觉敏感度受损。目标3：确定 化疗药物靶向默克尔椎间盘是否导致行为触觉障碍 回应。这一目标将决定化疗药物是否会损害胡须触觉行为 抑制默克尔盘5-羟色胺能传递的反应，以及是否增强默克尔盘 通过药物操纵5-羟色胺转运体的5-羟色胺能传递可以拯救受损的人 胡须触觉行为反应。♦完成这3个目标将填补关于触觉敏感度的科学空白 ，阐明CIPN麻木方面的新机制，并确定潜在的 拯救受损触觉敏感度的治疗靶点。

ABSTRACT: Tactile sensitivity of detecting gentle mechanical stimuli or touch is critically important in life but can be impaired to result in reduction/loss of tactile sensitivity (numbness) under pathological conditions. Numbness is the earliest and most common symptom of chemotherapy-induced peripheral neuropathy (CIPN) that negatively impacts quality of life in cancer patients, and it is a dose-limiting factor of chemotherapy. Numbness of CIPN is poorly treated and its underlying mechanism understudied. This lack of knowledge prevents development of effective management for numbness CIPN. ♦ A Merkel disc is a main type of tactile end organ located in touch sensitive spots throughout the body but most abundant at the human fingertips and whisker hair follicles of all non-primate mammals. A Merkel disc consists of a Merkel cell and an Aβ-afferent ending to form a synapse-like structure. We and others have recently discovered that tactile stimuli to Merkel discs are largely transduced in Merkel cells by Piezo2 channels, which drive most Aβ-afferent impulses and behavioral tactile responses. More recently, we have further identified that Merkel discs in whisker hair follicles are serotonergic synapses, and serotonin is released from Merkel cells in response to tactile stimuli to subsequently drive Aβ-afferent impulses and behavioral tactile responses. ♦ In this renewal application, our new focuses are to study how tactile sensitivity at Merkel discs is modulated and whether the tactile sensitivity can be impaired by chemotherapy drugs to account for the numbness aspect of CINP. ♦ We propose to use whisker hair follicle preparation to address these questions with 3 specific aims: Aim 1) Elucidate mechanisms underlying the modulation of Merkel disc tactile sensitivity. This Aim will focus on whether serotonin transporters play a key role in regulating Merkel disc serotonergic transmission and Merkel disc tactile sensitivity. Aim 2: Determine whether and how chemotherapy drugs impair Merkel disc tactile sensitivity. This Aim will measure changes of serotonergic transmission and Merkel disc tactile sensitivity following chemotherapy drug treatment, and identify pre- and postsynaptic molecules at Merkel discs that are targeted by chemotherapy drugs to result in the impairment of Merkel disc tactile sensitivity. Aim 3: Determine whether targeting Merkel discs by chemotherapy drugs leads to impairment of behavioral tactile responses. This Aim will determine whether chemotherapy drugs can impair whisker tactile behavioral responses via suppressing Merkel disc serotonergic transmission, and whether potentiation of Merkel disc serotonergic transmission by pharmacologically manipulating serotonin transporters can rescue the impaired whisker tactile behavioral responses. ♦ Completion of the 3 Aims will fill a scientific gap about tactile sensitivity of mammals, elucidate novel mechanisms underlying numbness aspect of CIPN, and identify potential therapeutic targets for rescuing impaired tactile sensitivity.