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:10525776
- 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 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:Action PotentialsAddressAdvisory CommitteesAffectAfferent NeuronsAttenuatedAwardBehaviorBehavioral AssayBiometryBiophysicsBrainClosure by clampCommunicationComplementConflict (Psychology)DataDetectionDevelopmentDevelopment PlansDiseaseElectrophysiology (science)EnsureEnvironmentEsthesiaEtiologyExperimental DesignsGeneticGoalsHealthHumanHyperalgesiaHypersensitivityIn Situ HybridizationIn VitroIndividualIon ChannelKnockout MiceKnowledgeLaboratoriesLeadLearningMammalsMediator of activation proteinMentorsMentorshipMolecularMusNatureNervous System PhysiologyNervous system structureNeuraxisNeuronsNeurosciencesOralPainPainlessPathway interactionsPeripheralPeripheral Nervous SystemPeripheral Nervous System DiseasesPharmacologyPhysiologicalPlayPositioning AttributePrevalenceProtein IsoformsResearchRoleSignal PathwaySignal TransductionSodium ChannelSpinal GangliaStatistical Data InterpretationStimulusTemperatureTestingTrainingTransgenic MiceTranslationsTrigeminal SystemWorkallodyniaavoidance behaviorbehavior testbiophysical propertiescareercareer developmentchronic constriction injurycold temperatureconditional knockoutexperienceexperimental studyhuman diseasein vivoinnovationinsightmechanical allodyniamouse modelmutantnatural hypothermianerve injurynew therapeutic targetnoveloxaliplatinpain modelpainful neuropathypatch clampperipheral nerve damagepre-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
有害的环境条件会对皮肤造成损害,并最终导致体温过低。尽管
寒冷感知的本质,即在体内传递寒冷信息的细胞和分子机制
外周背根神经节(DRG)感觉神经元的定位尚不明确。此外,周围神经
损伤通常会导致冷痛,这是一种对温和寒冷的温度过敏,目前尚不清楚
传递无害的寒冷信号的机制被劫持,或者相反,是分离的信号
道路都被占用了。在这份提案中,我们将通过调查一个新的角色来解决这些关键问题
电压门控钠通道,Nav1.1,在生理环境中传递寒冷信号,以及
在痛苦中。NAV1.1的体外药理抑制作用显著减弱动作电位放电
TRPM8-表达神经元,提供证据表明Nav1.1可能在体内冷感觉中起关键作用。我们有
开发了新的老鼠模型来测试Nav1.1通道传递寒冷信号的中心假设
尤其是在表达TRPM8的DRG神经元中,并在产生寒冷的疼痛状态下变得过度活跃
超感痛症。我们将使用条件基因敲除小鼠品系、不同体感的创新组合
来自基因鉴定的行为分析和机械膜片钳电生理实验
寒冷感觉神经元产生对两种疾病寒冷传递的外周机制的基本见解
健康和疾病。这项工作将促进我们对哺乳动物体温感觉的基本理解,并定义
Nav1.1在周围神经系统功能中的新角色。重要的是,拟议工作的完成是一项
朝着我的长期目标迈出了关键的一步,即开发一个领先的研究计划,解决基础和
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。至
为了实现这一目标,我制定了一份详细的职业发展计划,其中包括指导
委员会、科学咨询委员会和有针对性的专业发展活动,这些活动将侧重于:
1)获得行为分析和临床前疼痛范例方面的专业知识,2)获得高级生物统计学
分析技能,确保严谨的实验设计,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。根据该奖项接受的培训将
让我在躯体感觉神经科学领域开发一项成功的研究计划。
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:
10672978 - 财政年份:2022
- 资助金额:
$ 21.78万 - 项目类别:
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