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：
Theanne Nicole Griffith
金额：
$ 21.78万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
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：
https://reporter.nih.gov/project-details/10672978
关键词：
Action Potentials Address Advisory Committees Affect Afferent Neurons Attenuated Award Behavior Behavioral Assay Biometry Biophysics Brain Central Nervous System Closure by clamp Communication Complement Data Detection Development Development Plans Disease Electrophysiology (science)Ensure Environment Esthesia Etiology Experimental Designs Genetic Goals Health Human Hyperalgesia Hypersensitivity In Situ Hybridization In Vitro Individual Institution Ion Channel Knockout Mice Knowledge Laboratories Learning Mammals Mediator Mentors Mentorship Molecular Mus Nature Nervous System Nervous System Physiology Neurons Neurosciences Oral Pain Painless Pathway interactions Peripheral Peripheral Nervous System Peripheral Nervous System Diseases Physiological Play Positioning Attribute Prevalence Protein Isoforms Research Role SCN1A protein Signal Pathway Signal Transduction Sodium Channel Spinal Ganglia Statistical Data Interpretation Stimulus Temperature Testing Training Transgenic Mice Translations Trigeminal System Work Writing allodynia avoidance behavior behavior test biophysical properties career career development chronic constriction injury cold temperature conditional knockout experience experimental study human disease in vivo innovation insight mechanical allodynia mouse model mutant natural hypothermia nerve injury neurotransmission new therapeutic target novel oxaliplatin pain model painful neuropathy patch clamp peripheral nerve damage pharmacologic pre-clinical preference programs receptor skills skin damage somatosensory tool transcriptome sequencing transmission process voltage warm temperature

Action Potentials Address Advisory Committees Affect Afferent Neurons Attenuated Award Behavior Behavioral Assay Biometry Biophysics Brain Central Nervous System Closure by clamp Communication Complement Data Detection Development Development Plans Disease Electrophysiology (science)Ensure Environment Esthesia Etiology Experimental Designs Genetic Goals Health Human Hyperalgesia Hypersensitivity In Situ Hybridization In Vitro Individual Institution Ion Channel Knockout Mice Knowledge Laboratories Learning Mammals Mediator Mentors Mentorship Molecular Mus Nature Nervous System Nervous System Physiology Neurons Neurosciences Oral Pain Painless Pathway interactions Peripheral Peripheral Nervous System Peripheral Nervous System Diseases Physiological Play Positioning Attribute Prevalence Protein Isoforms Research Role SCN1A protein Signal Pathway Signal Transduction Sodium Channel Spinal Ganglia Statistical Data Interpretation Stimulus Temperature Testing Training Transgenic Mice Translations Trigeminal System Work Writing allodynia avoidance behavior behavior test biophysical properties career career development chronic constriction injury cold temperature conditional knockout experience experimental study human disease in vivo innovation insight mechanical allodynia mouse model mutant natural hypothermia nerve injury neurotransmission new therapeutic target novel oxaliplatin pain model painful neuropathy patch clamp peripheral nerve damage pharmacologic pre-clinical preference programs receptor skills skin damage somatosensory tool transcriptome sequencing transmission process voltage warm temperature

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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。寒冷温度的检测对于生存至关重要，允许避免有害环境条件会导致皮肤损伤并最终导致体温过低。尽管有冷感应的基本性质，将冷信息传输的细胞和分子机制外围背根神经节（DRG）感觉神经元的定义较差。而且，周围神经损害通常会导致寒冷的异常症，对温和温度的过敏，目前尚不清楚是否清楚是否清楚传递无害的冷信号的机制是高插座的，或者相反，单独的信号传导途径订婚。在此提案中，我们将通过调查新的角色来解决这些关键问题电压门控钠通道NAV1.1，在生理环境中传输冷信号以及在疼痛期间。 NAV1.1体外角色的药理抑制作用极大地削弱了动作潜在触发的动作表达TRPM8的神经元，提供证据表明NAV1.1对于体内冷感应至关重要。我们有开发了新的鼠标模型，以测试NAV1.1通道传输冷信号的中心假设特别是在表达TRPM8的DRG神经元中，并在产生冷的疼痛状态下变得过度活跃异常性。我们将使用有条件的敲除鼠标线的创新组合，多样的体感行为分析和机械贴钳电生理实验，来自遗传学的鉴定冷感应神经元以产生对两者中冷传播外围机制的基本见解健康与疾病。这项工作将提高我们对哺乳动物热敏度的基本理解并定义 NAV1.1在周围神经系统功能中的新作用。重要的是，拟议工作的完成是朝着制定领先的研究计划的长期目标的关键一步，该计划应对基本和翻译问题有关哺乳动物神经系统如何传输和编码热感觉。到完成这个目标，我制定了一项详细的职业发展计划，包括指导委员会，一个科学咨询委员会，针对专业发展活动，将重点关注： 1）在行为分析和临床前疼痛范式上获得专业知识，2）获得先进的生物统计学分析技能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和4）学习有效指导和实验室管理。根据该奖项获得的培训将独特地使我有望在体感神经科学领域制定成功的研究计划。