The role of TRPM8 and Nav1.8 channels in cold tolerance of hibernators

TRPM8和Nav1.8通道在冬眠动物耐冷能力中的作用

• 批准号: 9026719
• 负责人: Elena Gracheva
• 金额: $ 35.55万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-15 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9026719
• 关键词: Action Potentials; Acute; Affect; Analgesics; Animal Model; Animals; Area; Behavioral Paradigm; Bioinformatics; Biological; Blood; Body Temperature; Calcium; Cations; Cellular biology; Data; Detection; Development; Drops; Drug or chemical Tissue Distribution; Electrodes; Electrophysiology (science); Environment; Esthesia; Event; Ganglia; Genomics; Glean; Goals; Health; Heart Arrest; Hibernation; Human; Image; In Situ Hybridization; Ion Channel; Knowledge; Laboratories; Medical; Menthol; Modeling; Modification; Molecular; Mus; Neuraxis; Neurons; Outcome; Pain; Pathway interactions; Perception; Personal Satisfaction; Pharmacology; Phenotype; Physiologic Thermoregulation; Physiological; Physiology; Play; Process; Property; Protein Isoforms; RNA; RNA Splicing; Regulation; Resistance; Rodent; Role; Sensory; Signal Transduction; Sodium Channel; Spermophilus; Squirrel; Stimulus; Stroke; System; TRP channel; Temperature; Tetrodotoxin; Therapeutic; Trauma; Variant; allodynia; base; biophysical properties; chemotherapy; cold temperature; in vivo; insight; natural hypothermia; nerve injury; novel; novel strategies; painful neuropathy; patch clamp; post stroke; public health relevance; ratiometric; response; somatosensory; transcriptomics; transmission process; voltage; voltage clamp

 DESCRIPTION (provided by applicant): Thermosensitivity and thermotolerance are fundamental processes that affect virtually all aspects of human physiology. Human sensation of cold - ranging from refreshingly cool to unpleasant and frigid - relies on the ability of primar sensory afferents to transduce these stimuli into electrical signaling, thereby triggering adaptive biological response. Dysregulation of thermosensation underlie cold allodynia - a common hallmark of chemotherapy-, nerve injury- and post-stroke-induced neuropathic pain, in which even mild cooling can be perceived as excruciatingly painful. Despite significant medical relevance, the molecular aspects of cold sensation under normal, adaptive and pathological conditions, and the sequence of events that underlies this process still remain enigmatic and controversial. Animals that tune temperature sensitivity to the extreme provide ideal model to delineate cellular and molecular aspects of thermotolerance and temperature perception in general. We are using mammalian hibernation as a naturally-reversible model to understand these processes. Unlike the standard laboratory rodents, hibernating animals do not perceive cold temperature as uncomfortable until -2°C. This remarkable ability contributes to their unusual resistance to cold during hibernation, when the animals drop their core body temperature to 2-4°C. In this proposal, we are aiming to examine contribution of TRPM8 and Nav1.8 ion channels into cold adaptations in hibernating squirrels at the level of somatosensory system using multi-disciplinary approach, including physiology, imaging, behavioral paradigms, cell biology, differential transcriptomics, genomics and bioinformatics.

 描述（由应用提供）：热敏和热耐含量是影响人类生理学各个方面的基本过程。寒冷的人类感觉 - 从清爽到凉爽到不愉快和寒冷 - 依赖于主要感觉传入的能力将这些刺激转化为电信号，从而触发适应性 生物反应。热效率的失调基础是冷垂体的基础，这是化学疗法，神经损伤和中风后诱发的神经性疼痛的共同标志，即使温和的冷却甚至可能被认为是令人痛苦的痛苦。尽管有很大的医学相关性，但在正常，适应性和病理条件下冷感觉的分子方面以及该过程构成的事件的序列仍然是神秘的和有争议的。调节温度对极端敏感性的动物提供了理想的模型，以描绘一般而言的耐热性和温度感知的细胞和分子方面。我们将哺乳动物冬眠作为一种自然可逆的模型来了解这些过程。与标准的实验室杆不同，冬眠的动物直到-2°C直到-2°C才感到不舒服。当动物将其核心体温降低到2-4°C时，这种非凡的能力有助于他们在冬眠期间对冷的异常抗性。在此提案中，我们旨在研究使用多学科方法，包括生理学，成像，行为范式，生物学，差异转录组学，基因组学和生物学学，包括生理学，成像，行为范式，生物学，生物学，生物学，生物学，生物学，生物学，生物学，生物学，生物学，生物学，生物学，差异，，进行体感系统的水平，在体感系统的水平上进行冬眠小鼠的冷适应。