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
基本信息
- 批准号:10240307
- 负责人:
- 金额:$ 43.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAmyloid beta-ProteinAnimalsBehavioralCancer PatientChemosensitizationChemotherapy-induced peripheral neuropathyDataDevelopmentDose-LimitingDrug TargetingElectrophysiology (science)First Independent Research Support and Transition AwardsFunctional disorderGoalsHair follicle structureHumanImpairmentIon ChannelKnowledgeLeadLifeLightMammalsMeasuresMechanicsMerkel CellsMerkel&aposs CorpuscleMolecularNumbnessOrganPathogenesisPathologicPharmaceutical PreparationsPharmacologyPharmacotherapyPiezo 2 ion channelPlayPreparationPublic HealthPublishingQuality of lifeResearchSerotoninSpottingsStimulusStructureSynapsesTactileTestingTimeTouch sensationVibrissaebasebehavior testbehavioral impairmentbehavioral responsechemotherapycommon symptomnovelpostsynapticpreventresponsereuptakeserotonin transportertherapeutic targettransmission process
项目摘要
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:触觉灵敏度检测温和的机械刺激或触摸在生活中至关重要,
在病理条件下可能受损,导致触觉敏感性降低/丧失(麻木)。
麻木是化疗引起的周围神经病变(CIPN)最早和最常见的症状
对癌症患者的生活质量产生负面影响,并且是化疗的剂量限制因素。
CIPN的麻木治疗效果不佳,其潜在机制尚不清楚。人们缺乏了解
阻碍了麻木CIPN的有效管理。默克尔圆盘是一种主要类型的触觉
末端器官位于整个身体的触摸敏感点,但在人的指尖最丰富,
所有非灵长类哺乳动物的胡须毛囊。默克尔盘由默克尔细胞和Aβ传入纤维组成
最终形成一个类似突触的结构。我们和其他人最近发现对默克尔的触觉刺激
椎间盘在默克尔细胞中主要通过Piezo 2通道转导,Piezo 2通道驱动大多数Aβ传入冲动,
行为触觉反应最近,我们进一步确定了胡须毛囊中的默克尔盘
是羟色胺能突触,5-羟色胺从默克尔细胞释放,以响应触觉刺激,
随后驱动Aβ传入冲动和行为触觉反应。在此更新申请中,我们的
研究默克尔盘的触觉敏感性是如何调节的,以及触觉敏感性是否
化疗药物可能会削弱CINP的麻木感。我们建议使用
胡须毛囊准备,以解决这些问题,有3个具体目标:目标1)阐明
默克尔盘触觉敏感性调制的潜在机制。这一目标将侧重于是否
5-羟色胺转运体在调节默克尔椎间盘神经递质传递和默克尔椎间盘神经递质传递中起关键作用。
触觉灵敏度目的2:确定化疗药物是否以及如何损害默克尔椎间盘触觉
灵敏度该目的将测量神经传导和默克尔椎间盘触觉敏感性的变化
化疗药物治疗后,并确定突触前和突触后分子在默克尔光盘,
被化疗药物靶向,导致默克尔盘触觉敏感性受损。目标3:确定
通过化疗药物靶向默克尔椎间盘是否会导致行为触觉损伤
应答本研究旨在确定化疗药物是否会损害触须触觉行为
通过抑制默克尔盘神经元能传递的反应,以及是否增强了默克尔盘神经元能传递,
通过操纵5-羟色胺转运体的多巴胺能传递可以挽救受损的
触须触觉行为反应。3个目标的完成将填补触觉灵敏度的科学空白
阐明CIPN麻木方面的新机制,并确定潜在的
用于挽救受损的触觉敏感性的治疗目标。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('JIANGUO GU', 18)}}的其他基金
Ion channels and their functions at the node of Ranvier of mammalian somatosensory afferent fibers
哺乳动物体感传入纤维朗飞节离子通道及其功能
- 批准号:
10551875 - 财政年份:2019
- 资助金额:
$ 43.93万 - 项目类别:
Ion channels and their functions at the node of Ranvier of mammalian somatosensory afferent fibers
哺乳动物体感传入纤维朗飞节离子通道及其功能
- 批准号:
10322385 - 财政年份:2019
- 资助金额:
$ 43.93万 - 项目类别:
Cellular and ion channel mechanisms underlying the sense of light touch in mammal
哺乳动物光触觉的细胞和离子通道机制
- 批准号:
9306012 - 财政年份:2014
- 资助金额:
$ 43.93万 - 项目类别:
Mechanism of Nociception Induced by Innocuous Cold in Trigeminal System
无害寒冷引起三叉神经痛觉的机制
- 批准号:
8984706 - 财政年份:2014
- 资助金额:
$ 43.93万 - 项目类别:
Mechanism of Nociception Induced by Innocuous Cold in Trigeminal System
无害寒冷引起三叉神经痛觉的机制
- 批准号:
9280916 - 财政年份:2014
- 资助金额:
$ 43.93万 - 项目类别:
Cellular and ion channel mechanisms underlying the sense of light touch in mammal
哺乳动物光触觉的细胞和离子通道机制
- 批准号:
8862182 - 财政年份:2014
- 资助金额:
$ 43.93万 - 项目类别:
Mechanism of Nociception Induced by Innocuous Cold in Trigeminal System
无害寒冷引起三叉神经痛觉的机制
- 批准号:
8887324 - 财政年份:2014
- 资助金额:
$ 43.93万 - 项目类别:
Cellular and ion channel mechanisms underlying the sense of light touch in mammal
哺乳动物光触觉的细胞和离子通道机制
- 批准号:
9095850 - 财政年份:2014
- 资助金额:
$ 43.93万 - 项目类别:
Cellular and ion channel mechanisms underlying the sense of light touch in mammal
哺乳动物光触觉的细胞和离子通道机制
- 批准号:
8576721 - 财政年份:2013
- 资助金额:
$ 43.93万 - 项目类别:
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:
9754107 - 财政年份:2013
- 资助金额:
$ 43.93万 - 项目类别:
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