Molecular and cellular basis of reversible hypothermia

可逆低温的分子和细胞基础

• 批准号: 10583822
• 负责人: Elena Gracheva
• 金额: $ 51.53万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-05 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583822
• 关键词: Ablation; Acute; Affect; Animal Model; Animals; Arousal; Blood; Body Temperature; Brain; Brown Fat; Complex; Cutaneous; Data; Detection; Development; Drops; Electrophysiology (science); Fiber; Glean; Goals; Hamsters; Heart; Heart Arrest; Hibernation; Histology; Homeostasis; Hour; Human; Hypothalamic structure; Ion Channel; Knock-out; Knowledge; Laboratories; Laboratory mice; Lesion; Maintenance; Mammals; Measurement; Metabolism; Modeling; Molecular; Molecular Evolution; Monitor; Mus; Nature; Nerve Tissue; Neurons; Orthologous Gene; Output; Pathologic; Pathway interactions; Personal Satisfaction; Pharmacology; Phenotype; Photometry; Physiologic Thermoregulation; Physiological; Physiology; Preoptic Areas; Process; Respiration; Role; Salivary Glands; Skeletal Muscle; Spermophilus; Squirrel; Stroke; Structure; System; Temperature; Temperature Sense; Testing; Therapeutic; Thermogenesis; Tissues; Trauma; Visceral; Work; behavior test; biophysical analysis; biophysical properties; comparative; experimental study; in vivo; induced hypothermia; insight; interdisciplinary approach; mutant; natural hypothermia; novel; optogenetics; pharmacologic; response; sensor; somatosensory; tool; virtual

Project summary Thermoregulation is a fundamental process that affects virtually all aspects of animal physiology. In mammals, core body temperature is monitored by neurons in the preoptic area of the hypothalamus. Activity of these neurons determines the neuronal output that drives thermoregulation and controls body temperature. Despite its fundamental physiological significance, the molecular basis of temperature homeostasis under normal, adaptive and pathological conditions remains obscure. Mammalian hibernation is a cyclical reprograming of a thermoregulatory phenotype. This process is associated with dramatic physiological perturbations: heart and respiration rate decrease, core body temperature drops from 37°C to 2- 4°C. Upon arousal from hibernation, all physiological parameters return to normal within hours. This remarkable plasticity suggests the presence of specific adaptations in the thermoregulatory system of hibernators, but the underlying cellular and molecular mechanisms remain enigmatic. In this basic scientific proposal, we will employ a comparative multidisciplinary approach to understand cellular and molecular principles of reversible hypothermia at the level of POA, using a novel hypothermia-tolerant animal model, hibernating thirteen-lined ground squirrel, and laboratory mice, a non-hibernating species. Understanding how hibernators achieve reversible hypothermia will facilitate the development of pharmacology to induce and regulate hypothermia in mammals.

项目摘要 体温调节是影响动物生理学几乎所有方面的基本过程。 在哺乳动物中，核心体温是由视前区的神经元监测的。 下丘脑这些神经元的活动决定了神经元的输出， 体温调节和控制体温。尽管其基本的生理 重要性，温度稳态的分子基础下，正常，适应性和 病理状况仍然不清楚。哺乳动物的冬眠是一种周期性的 体温调节表型这一过程与戏剧性的生理 扰动：心脏和呼吸频率降低，核心体温从37°C降至2- 4°C。一旦从冬眠中醒来，所有的生理参数都会在几个小时内恢复正常。 这种显著的可塑性表明在体温调节中存在着特殊的适应性。 冬眠系统，但潜在的细胞和分子机制仍然是谜。 在这个基本的科学建议中，我们将采用比较多学科的方法， 了解可逆性低温在POA水平的细胞和分子原理，使用 一种新的耐低氧动物模型，冬眠的十三线地松鼠， 实验室小鼠，一种非冬眠物种。了解冬眠如何实现可逆 低温将促进诱导和调节低温的药理学的发展 在哺乳动物中。