TRP-like channel ANKTM1 in vivo

体内 TRP 样通道 ANKTM1

• 批准号: 6837471
• 负责人: GINA M STORY
• 金额: $ 4.89万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6837471
• 关键词: RNA interference; behavior test; calcium channel; cell line; cold temperature; fluorescence microscopy; fluorescent dye /probe; genetically modified animals; laboratory mouse; laboratory rat; neurophysiology; nociceptors; pain; postdoctoral investigator; protein structure function; salicylate; spinal ganglion

DESCRIPTION (provided by applicant): Several TRP channels have been shown to be directly gated by thermal stimuli. TRPV1, the first temperature-activated TRP identified, responds to noxious heat (42C) and to capsaicin and is specifically expressed in a subset of nociceptive (pain sensing) neurons in the dorsal root ganglia (DRG). TRPM8, expressed in a separate population of neurons in the DRG, responds to cool temperatures (25C) and to menthol. Their distinct sensory modalities and expression patterns suggest that TRPV1 and TRPM8 transmit "hot" and "cool" signals via different pathways. Recently I identified ANKTM1, a TRP-like channel that responds to noxious cold temperatures (17C) and is expressed in a subset of nociceptive neurons that also express TRPV1. I also identified DRG neurons in culture that respond to both noxious heat and cold, but not to menthol, suggesting neurons that transmit a cool/pleasant signal are separate from those that convey both noxious heat and cold. I therefore propose that together TRPV1 and ANKTM1 mark "polymodal nociceptors," neurons that transmit several painful modalities. The central hypothesis of this proposal is that ANKTM1 activation in sensory neurons elicits a painful signal in vivo. This hypothesis is based on preliminary data that Methyl Salicylate, a specific activator of ANKTM1, causes nociceptive behaviors in mice. The broad objective of this proposal is to examine the consequences of ANKTM1 activation by using Methyl Salicylate as a sensory readout. The aims of the proposal apply RNAi in cultured neurons and behavioral assays and gene knockout in mice. These studies will further elucidate the role of ANKTM1 in temperature and pain detection.

描述（由申请人提供）：多个 TRP 通道已被证明是由热刺激直接门控的。 TRPV1 是第一个被识别的温度激活 TRP，它对有害热量 (42°C) 和辣椒素有反应，并且在背根神经节 (DRG) 的伤害感受（疼痛感知）神经元子集中特异性表达。 TRPM8 在 DRG 中的单独神经元群中表达，对低温 (25°C) 和薄荷醇有反应。它们独特的感觉模式和表达模式表明TRPV1和TRPM8通过不同的途径传递“热”和“冷”信号。最近，我发现了 ANKTM1，一种类似 TRP 的通道，可对有害的低温 (17°C) 做出反应，并在也表达 TRPV1 的伤害性神经元子集中表达。我还在培养物中发现了对有害热和冷都有反应的 DRG 神经元，但对薄荷醇没有反应，这表明传递凉爽/愉快信号的神经元与那些传递有害热和冷信号的神经元是分开的。因此，我建议 TRPV1 和 ANKTM1 一起标记“多模式伤害感受器”，即传递多种疼痛模式的神经元。该提议的中心假设是感觉神经元中的 ANKTM1 激活会在体内引发疼痛信号。这一假设基于初步数据，即 ANKTM1 的特异性激活剂水杨酸甲酯会引起小鼠伤害性行为。该提案的主要目标是通过使用水杨酸甲酯作为感官读数来检查 ANKTM1 激活的后果。该提案的目的是将 RNAi 应用于培养的神经元以及小鼠的行为测定和基因敲除。这些研究将进一步阐明ANKTM1在温度和疼痛检测中的作用。