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

哺乳动物轻触感的细胞和离子通道机制

• 批准号: 10240307
• 负责人: JIANGUO GU
• 金额: $ 43.93万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2023-06-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240307
• 关键词: Address; Amyloid beta-Protein; Animals; Behavioral; Cancer Patient; Chemosensitization; Chemotherapy-induced peripheral neuropathy; Data; Development; Dose-Limiting; Drug Targeting; Electrophysiology (science); First Independent Research Support and Transition Awards; Functional disorder; Goals; Hair follicle structure; Human; Impairment; Ion Channel; Knowledge; Lead; Life; Light; Mammals; Measures; Mechanics; Merkel Cells; Merkel' s Corpuscle; Molecular; Numbness; Organ; Pathogenesis; Pathologic; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Piezo 2 ion channel; Play; Preparation; Public Health; Publishing; Quality of life; Research; Serotonin; Spottings; Stimulus; Structure; Synapses; Tactile; Testing; Time; Touch sensation; Vibrissae; base; behavior test; behavioral impairment; behavioral response; chemotherapy; common symptom; novel; postsynaptic; prevent; response; reuptake; serotonin transporter; therapeutic target; transmission process

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.

摘要：检测温和的机械刺激或触摸的触觉灵敏度在生活中至关重要，但 可以损害会导致病理条件下触觉灵敏度（麻木）的降低/降低。 麻木是化学疗法引起的周围神经病（CIPN）的最早，最常见的症状 这会对癌症患者的生活质量产生负面影响，并且是化学疗法的剂量限制因素。 CIPN的麻木性治疗不佳，其基本机制也被理解。缺乏知识 防止开发有效的麻木CIPN的管理。 ♦默克尔光盘是一种主要的触觉 末端器官位于整个身体的触摸敏感斑点，但在人的指尖和 所有非青睐的哺乳动物的晶须毛发卵泡。默克尔圆盘由默克尔细胞和Aβ代表组成 结束以形成突触样结构。我们和其他人最近发现了对默克尔的触觉刺激 盘子在默克尔细胞中通过压电2通道大量翻译，这些通道驱动大多数Aβ型脉冲，并且 行为触觉响应。最近，我们进一步确定了晶须毛囊中的默克尔椎间盘 是5-羟色胺突触，以及羟色胺从默克尔细胞中释放，以响应触觉刺激 随后，驱动Aβ的冲动和行为触觉反应。 ♦在此续签应用中，我们的 新的重点是研究如何调节默克尔碟片的触觉灵敏度以及是否触觉敏感性 化学疗法药物可能会损害，以说明辛普的麻木方面。 ♦我们建议使用 晶须毛囊准备以3个特定目的解决这些问题：目标1）阐明 默克尔盘式触觉灵敏度调制的基础机制。这个目标将集中于是否 5-羟色胺转运蛋白在调节默克尔唱片5-羟色源性传播和默克尔盘方面起关键作用 触觉灵敏度。目标2：确定化学疗法药物是否以及如何损害默克尔碟形触觉 灵敏度。该目标将衡量血清素能传播和默克尔盘式触觉的变化 化学疗法治疗后，并在默克尔椎间盘上识别出突触前和后分子 由化学疗法药物靶向，导致默克尔盘触觉敏感性受损。目标3：确定 化学疗法药物靶向默克尔椎间盘是否会导致行为触觉损害 回答。这个目标将决定化疗药物是否会损害晶须触觉行为 通过抑制默克尔唱片血清素能传播以及默克尔盘是否增强的响应 通过药物操纵5-羟色胺转运蛋白的血清素能传播可以挽救受损的 晶须触觉行为反应。 ♦完成3个目标的完成将填补有关触觉灵敏度的科学差距 哺乳动物，阐明CIPN麻木方面的新机制，并确定潜力 挽救触觉敏感性受损的治疗靶标。