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: 9312901
• 负责人: Elena Gracheva
• 金额: $ 45.97万
• 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/9312901
• 关键词: Action Potentials; Acute; Affect; Analgesics; Animal Model; Animals; Area; Behavioral Paradigm; Bioinformatics; Biological; Biophysics; 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; Pathologic; Pathway interactions; Perception; Periodicity; 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; interdisciplinary approach; natural hypothermia; nerve injury; novel; novel strategies; painful neuropathy; patch clamp; post stroke; public health relevance; ratiometric; response; somatosensory; transcriptomics; transmission process; virtual; 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（由申请人提供）：热敏感性和耐热性是影响人类生理学几乎所有方面的基本过程，从清爽的凉爽到令人不快和寒冷，依赖于初级感觉传入将这些刺激转换为电的能力。信令，从而触发自适应 冷异常性疼痛是热感觉失调的基础，这是化疗、神经损伤和中风后引起的神经性疼痛的常见特征，其中即使是轻微的冷却也可以被认为是极其痛苦的，尽管具有显着的医学相关性，但从分子角度来看。正常、适应性和病理条件下的冷感觉，以及这一过程背后的事件顺序仍然是神秘和有争议的，将温度敏感性调节到极端的动物为描述细胞和分子方面提供了理想的模型。我们使用哺乳动物冬眠作为自然可逆的模型来理解这些过程，与标准实验室啮齿类动物不同，冬眠动物在 -2°C 之前不会感觉到寒冷的温度。冬眠期间，当动物的核心体温降至 2-4°C 时，它们对寒冷具有异常的抵抗力。在本提案中，我们的目标是研究 TRPM8 和 Nav1.8 离子通道对寒冷适应的贡献。使用多学科方法，包括生理学、成像、行为范式、细胞生物学、差异转录组学、基因组学和生物信息学，在体感系统水平上冬眠松鼠。