A Novel Role for Nav1.1 in Mammalian Thermosensation

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TRPM 8的背根神经节神经元中，并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。

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.