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

 描述(申请人提供)：热敏性和耐热性是影响人体生理学几乎所有方面的基本过程。人类对寒冷的感觉--从令人耳目一新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化为电信号的能力，从而触发适应性 生物反应。体温调节失调是冷痛、神经损伤和中风后神经病理性疼痛的根本原因，冷痛是化疗的一个共同标志，在中风后，即使是轻微的降温也会被认为是极度疼痛的。尽管有重要的医学意义，但在正常、适应和病理条件下的冷感的分子方面，以及这一过程背后的事件序列仍然是一个谜，也是有争议的。将温度敏感度调整到极端的动物提供了理想的模型来描绘细胞和分子方面的耐热性和一般的温度感知。我们正在使用哺乳动物冬眠作为一个自然可逆的模型来理解这些过程。与标准的实验室啮齿动物不同，冬眠动物直到零下2摄氏度才会感觉寒冷不舒服。这种非凡的能力有助于它们在冬眠期间对寒冷的异常抵抗力，当动物的核心体温下降到2-4摄氏度时，在这项建议中，我们旨在利用多学科的方法，包括生理学、成像、行为范式、细胞生物学、差异转录学、基因组学和生物信息学，在体感系统水平上研究TRPM8和Nav1.8离子通道在冬眠松鼠冷适应中的作用。

 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.