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。

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.