Molecular basis of cold tolerance

生物体如何感知和适应寒冷的温度？耐冷性是温度敏感性的一个特殊方面，是与所有动物相关的一种关键生理能力。在正常和适应条件下，有助于检测和调节冷敏感性的分子机制尚未完全阐明。该项目旨在通过研究耐寒动物、13只地松鼠和叙利亚仓鼠，从一个新的角度看待寒冷敏感的一般问题。除了在冬眠期间抵御深冷的能力外，松鼠和仓鼠即使在夏季活动状态下也能耐寒。该项目试图通过对松鼠、仓鼠和小鼠的生理机制进行并列比较来了解耐寒的细胞和分子基础。这项研究将突出形成耐寒能力的进化变化，并阐明包括人类在内的脊椎动物感知寒冷的生理学基础的基本原理。该项目采用多学科方法，涉及行为范式、活细胞成像、细胞生物学和离子通道的体外生物物理分析，以解决这一基本的生物学问题。该协会还将举办一个创新的“感觉生理学俱乐部”，作为一项核心外展活动。该俱乐部的使命是在初中生和高中生中推广人和动物生理学的科学教育。本活动将向来自康涅狄格州、纽约和马萨诸塞州的学龄儿童讲授感觉生物学和感知感官刺激的神经机制方面的知识。与耶鲁大学科学之路和学者计划建立的合作将有助于招募参与者并监测该计划的长期影响。这项研究的主要目标是了解哺乳动物冬眠动物、13只地松鼠和叙利亚仓鼠对冷敏感的分子基础。对冷敏感和耐寒动物的比较将揭示支持冬眠的解剖、生理和遗传因素，冬眠是一种独特的热适应过程。为了研究活动性冬眠者躯体感觉系统中温度传感器的丰度，并将其与非冬眠物种小鼠进行比较，将采用组织学分析和初级感觉神经元活细胞比率钙成像。已知，Nav1.7是一种电压门控钠通道，负责体感神经元动作电位的起始和传播。该提案将利用异种细胞和神经元中的电生理记录来测试松鼠和仓鼠Nav1.7同源基因的生物物理特性。这项提议的成功完成将突出耐冷性的分子和细胞基础，并揭示一种由Nav1.7介导的控制哺乳动物冬眠中寒冷温度适应的新机制。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

How do organisms sense and adapt to cold temperature? Cold tolerance, a special aspect of temperature sensitivity, is a key physiological capacity pertinent to all animals. Molecular mechanisms that contribute to the detection and modulation of cold sensitivity under normal and adaptive conditions are yet to be fully elucidated. This project aims to look at the general problem of cold sensitivity from a novel perspective - through studying cold-tolerant animals, thirteen-lined ground squirrels and Syrian hamsters. In addition to their ability to withstand deep cold during hibernation, squirrels and hamsters are cold tolerant even in the summer active state. This project seeks to understand the cellular and molecular basis of cold tolerance by performing a side-by-side comparison of physiological mechanisms in the squirrels, hamsters and mice. This research will highlight evolutionary changes that shaped cold tolerance and elucidate basic principles that underlie physiology of cold perception in vertebrates including humans. This project takes a multidiscplinary approach, involving behavioral paradigms, live-cell imaging, cell biology and in vitro biophysical analysis of ion channels to address this fundamental biological question. The PI will also run an innovative "Sensory Physiology Club" as a core outreach activity. The mission of the Club is to promote scientific education in human and animal physiology among school students from middle- and high schools. This activity will teach aspects of sensory biology and neural mechanisms underlying perception of sensory stimuli to school-aged children from Connecticut, New York and Massachusetts. An established collaboration with the Yale Pathways to Science and SCHOLAR programs, will serve to recruit participants and to monitor long-term impact of this program.The major goal of this study is to understand the molecular basis of cold sensitivity in mammalian hibernators, thirteen-lined ground squirrels and Syrian hamsters. A comparison of cold-sensitive and cold-tolerant animals will reveal anatomical, physiological, and genetic factors that support hibernation, a unique thermo-adaptive process. To investigate the abundance of temperature sensors in somatosensory system in active hibernators and compare it to mice, a non-hibernating species, histological analysis and live cell ratiometric calcium imaging of primary sensory neurons will be employed. It is known that Nav1.7 is a voltage-gated sodium channel responsible for initiation and propagation of action potential in somatosensory neurons. The proposal will test biophysical properties of squirrel and hamster Nav1.7 orthologues using electrophysiological recordings in heterologous cells and in neurons. Successful completion of this proposal will highlight molecular and cellular basis of cold tolerance and reveal a novel Nav1.7-mediated mechanism controlling cold temperature adaptations in mammalian hibernators.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.