A Novel Role for Nav1.1 in Mammalian Thermosensation
Nav1.1 在哺乳动物热感觉中的新作用
基本信息
- 批准号:10672978
- 负责人:
- 金额:$ 21.78万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-08-01 至 2027-07-31
- 项目状态:未结题
- 来源:
- 关键词:Action PotentialsAddressAdvisory CommitteesAffectAfferent NeuronsAttenuatedAwardBehaviorBehavioral AssayBiometryBiophysicsBrainCentral Nervous SystemClosure by clampCommunicationComplementDataDetectionDevelopmentDevelopment PlansDiseaseElectrophysiology (science)EnsureEnvironmentEsthesiaEtiologyExperimental DesignsGeneticGoalsHealthHumanHyperalgesiaHypersensitivityIn Situ HybridizationIn VitroIndividualInstitutionIon ChannelKnockout MiceKnowledgeLaboratoriesLearningMammalsMediatorMentorsMentorshipMolecularMusNatureNervous SystemNervous System PhysiologyNeuronsNeurosciencesOralPainPainlessPathway interactionsPeripheralPeripheral Nervous SystemPeripheral Nervous System DiseasesPhysiologicalPlayPositioning AttributePrevalenceProtein IsoformsResearchRoleSCN1A proteinSignal PathwaySignal TransductionSodium ChannelSpinal GangliaStatistical Data InterpretationStimulusTemperatureTestingTrainingTransgenic MiceTranslationsTrigeminal SystemWorkWritingallodyniaavoidance behaviorbehavior testbiophysical propertiescareercareer developmentchronic constriction injurycold temperatureconditional knockoutexperienceexperimental studyhuman diseasein vivoinnovationinsightmechanical allodyniamouse modelmutantnatural hypothermianerve injuryneurotransmissionnew therapeutic targetnoveloxaliplatinpain modelpainful neuropathypatch clampperipheral nerve damagepharmacologicpre-clinicalpreferenceprogramsreceptorskillsskin damagesomatosensorytooltranscriptome sequencingtransmission processvoltagewarm temperature
项目摘要
Project Summary. Detection of cold temperatures is fundamental for survival and allows for avoidance of
harmful environmental conditions that produce skin damage and eventually lead to hypothermia. Despite the
essential nature of cold sensing, the cellular and molecular mechanisms that transmit cold information in
peripheral dorsal root ganglion (DRG) sensory neurons remain poorly defined. Moreover, peripheral nerve
damage often results in cold allodynia, a hypersensitivity to mildly cold temperatures, and it is unclear whether
the mechanisms that transmit innocuous cold signals are highjacked or if conversely, separate signaling
pathways are engaged. In this proposal, we will address these critical questions by investigating a novel role for
the voltage-gated sodium channel, NaV1.1, in transmitting cold signals in a physiological context, as well as
during pain. Pharmacological inhibition of NaV1.1 in vitro role drastically attenuates action potential firing in
TRPM8-expressing neurons, providing evidence that NaV1.1 may be critical for cold-sensing in vivo. We have
developed new mouse models to test the central hypothesis that NaV1.1 channels transmit cold signals
specifically in TRPM8-expressing DRG neurons and become overactive during pain states that produce cold
allodynia. We will use an innovative combination of conditional knockout mouse lines, diverse somatosensory
behavioral assays, and mechanistic patch-clamp electrophysiological experiments from genetically identified
cold-sensing neurons to generate fundamental insights into peripheral mechanisms of cold transmission in both
health and disease. This work will advance our basic understanding of mammalian thermosensation and define
a new role for NaV1.1 in peripheral nervous system function. Importantly, completion of the proposed work is a
critical step towards my long-term goal of developing a leading research program that tackles basic and
translation questions about how the mammalian nervous system transmits and encodes thermal sensations. To
accomplish this goal, I have developed a detailed career development plan that includes a mentorship
committee, a scientific advisory committee, and targeted professional development activities that will focus on:
1) gaining expertise in behavioral assays and preclinical pain paradigms, 2) acquiring advanced biostatistical
analysis skills to ensure rigorous experimental design, 3) refining my written and oral scientific communication
skills, and 4) learning effective mentorship and lab management. The training received under this award will
uniquely poise me to develop a successful research program in the field of somatosensory neuroscience.
项目摘要。检测寒冷的温度是生存的基础,并允许避免
有害的环境条件,产生皮肤损伤并最终导致体温过低。尽管
冷感的本质,细胞和分子机制,传递冷信息,
外周背根神经节(DRG)感觉神经元仍然不清楚。此外,外周神经
损伤通常导致冷异常性疼痛,对轻度寒冷温度的超敏反应,
传输无害冷信号的机制被劫持,或者相反,单独的信令
道路被占用。在本提案中,我们将通过调查一种新的作用来解决这些关键问题,
电压门控钠通道NaV1.1在生理环境中传递冷信号,以及
在痛苦中。NaV1.1在体外作用的药理学抑制显著减弱了神经细胞的动作电位放电。
TRPM8表达神经元,提供证据表明NaV1.1可能是体内冷感知的关键。我们有
开发了新的小鼠模型来测试中心假设,即NaV1.1通道传递冷信号
特别是在表达TRPM8的DRG神经元中,并且在产生寒冷的疼痛状态期间变得过度活跃,
异常性疼痛我们将采用创新组合的条件性基因敲除小鼠品系,
行为分析和机械膜片钳电生理实验,从遗传鉴定
冷感觉神经元产生的基本见解冷传输的外周机制,在这两个
健康和疾病。这项工作将推进我们对哺乳动物温度感觉的基本理解,并定义
NaV1.1在周围神经系统功能中的新作用。重要的是,完成拟议的工作是一个
我的长期目标是发展一个领先的研究计划,解决基本和关键的一步,
关于哺乳动物神经系统如何传递和编码热感觉的翻译问题。到
为了实现这一目标,我制定了一个详细的职业发展计划,其中包括一个导师制
委员会、科学咨询委员会和有针对性的专业发展活动,重点是:
1)获得行为分析和临床前疼痛范例的专业知识,2)获得先进的生物统计学
分析技能,以确保严格的实验设计,3)完善我的书面和口头科学交流
技能,以及4)学习有效的指导和实验室管理。在该奖项下接受的培训将
在躯体感觉神经科学领域,我有独特的优势来开发一个成功的研究项目。
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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Theanne Nicole Griffith其他文献
Theanne Nicole Griffith的其他文献
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{{ truncateString('Theanne Nicole Griffith', 18)}}的其他基金
Mapping the Pain Landscape: From Molecules to Medicine
绘制疼痛图谱:从分子到医学
- 批准号:
10609162 - 财政年份:2023
- 资助金额:
$ 21.78万 - 项目类别:
A Novel Role for Nav1.1 in Mammalian Thermosensation
Nav1.1 在哺乳动物热感觉中的新作用
- 批准号:
10525776 - 财政年份:2022
- 资助金额:
$ 21.78万 - 项目类别:
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