Biology and applications of mammalian hibernation-like states

哺乳动物冬眠状态的生物学和应用

• 批准号: 10473207
• 负责人: Sinisa Hrvatin
• 金额: $ 175.5万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10473207
• 关键词: Animals; Award; Behavior; Biology; Blood; Blood Circulation; Body Temperature; Breathing; Cancer Biology; Cell Survival; Cells; Complex; Critical Care; Degenerative Disorder; Disease Progression; Environment; Food; Foundations; Future; Genetic; Growth; Heart Arrest; Heart Rate; Hibernation; Hour; Human; Hypothalamic structure; Hypoxia; Laboratory mice; Life; Malignant Neoplasms; Medical; Medicine; Metabolic Diseases; Metabolism; Monitor; Movement; Mus; Nature; Nerve Degeneration; Neurons; Organ; Organism; Pathway interactions; Physiological; Physiology; Planet Earth; Population; Primates; Principal Investigator; Role; Stress; Stroke; Time; Transgenic Organisms; Trauma; Work; behavioral study; cancer therapy; chemotherapy; energy balance; experimental study; fascinate; human tissue; innovation; metabolic rate; neonatal care; neuronal circuitry; nonhuman primate; novel; novel strategies; prevent; programs; tool

Program Director/Principal Investigator (Last, First, Middle): Hrvatin, Sinisa Project Summary: Life on Earth has evolved fascinating adaptations such as torpor and hibernation to survive extreme environments. These extraordinary adaptations are characterized by profoundly decreased physiological functions, including metabolic rate, body temperature, circulation, breathing, and heart-rate. How warm-blooded animals enter, regulate, and survive these states remains one of the most fascinating mysteries of homeotherm biology, the understanding of which could have profound implications on human medicine. Investigating, for example, the mechanisms that adaptively modulate metabolism could provide new approaches to regulate human energy balance and treat metabolic diseases. An induced hypothermic and hypometabolic state could slow down disease progression, for example cancer growth. The pathways that enable cells and organs in torpor and hibernation to survive hypoxic and hypothermic stress might also be harnessed to facilitate cell survival during trauma, stroke, cardiac arrest, chemotherapy, or even neurodegeneration. Among the species naturally capable of entering these states are laboratory mice. Mice placed in environments devoid of food initiate torpor - a behavior characterized by bouts of greatly reduced core body temperature, movement, and metabolic rate, lasting several hours. Recently, employing novel transgenic tools and sequencing approaches, we examined this complex behavior and discovered that mouse torpor is regulated by a distinct population of neurons in the hypothalamus. Inhibiting these neurons prevents natural torpor and stimulating them rapidly decreases metabolic rate and body temperature, inducing a torpor-like state. This discovery forms the foundation for future explorations of mechanisms regulating torpor and hibernation, enabling for the first time genetic access to monitor, initiate, manipulate, and study these behaviors. In this proposal, we investigate key unanswered questions in the field of torpor and hibernation and explore potential applications for induced hibernation-like states in cancer biology. Specifically, we examine the neuronal circuit that regulates the decrease in body temperature and metabolic rate and explore the role of circulating factors in inducing this organism-wide state. We pioneer a new approach to induce a long-term hibernation-like state in mice, explore mammalian physiology in this state, and examine the impact of this state on cancer growth and protection from chemotherapy. Finally, we investigate the evolutionary conservation of torpor-regulating neurons across species including in non-human primates and human tissues and examine whether a torpor-like state can be induced in a non-human primate, paving the way to potential human applications. This proposal is bold and ambitious; however, each of the proposed projects contains clearly defined and feasible experiments whose results have the potential to greatly advance, if not transform, our understanding of torpor, hibernation, and homeotherm biology. The innovative and early-stage nature of this work, along with its potential to advance medical treatment, makes it ideally suited for the New Innovator Award.

项目负责人/主要研究者（最后，第一，中间）：Hrvatin，Sinisa 项目概要： 地球上的生命已经进化出了令人着迷的适应性，如麻木和冬眠，以生存在极端的环境中。 环境.这些非凡的适应性的特征是， 功能，包括代谢率，体温，循环，呼吸和心率。多么热血 动物进入、调节和生存这些状态仍然是恒温动物最迷人的奥秘之一 生物学，对它的理解可能对人类医学产生深远的影响。调查，为 例如，适应性调节代谢的机制可以提供新的方法来调节 人体能量平衡和治疗代谢疾病。诱导的低温和低代谢状态可能 减缓疾病进展，例如癌症生长。使细胞和器官处于休眠状态的途径 而冬眠在缺氧和低温的压力下存活也可能被利用来促进细胞的存活 在创伤、中风、心脏骤停、化疗、甚至神经退行性疾病中。在自然界中 能够进入这些状态的是实验室老鼠。置于缺乏食物环境中的小鼠开始麻木 - 一种以核心体温、运动和代谢率大幅降低为特征的行为， 持续数小时。最近，采用新的转基因工具和测序方法，我们研究了 这一复杂的行为，并发现老鼠的麻木是由一个独特的神经元群体在调节， 下丘脑抑制这些神经元可以防止自然的麻痹，刺激它们可以迅速降低代谢 率和体温，诱导torpor-like状态。这一发现为未来的研究奠定了基础 探索调节休眠和冬眠的机制，首次使基因能够获得 监控、发起、操纵和研究这些行为。在这份提案中，我们调查了未回答的关键问题， 问题在该领域的麻痹和冬眠，并探讨潜在的应用诱导冬眠样 在癌症生物学中。具体来说，我们研究了调节身体减少的神经回路， 温度和代谢率，并探讨循环因素在诱导这种生物体范围内的状态的作用。 我们开创了一种新的方法，诱导小鼠长期冬眠样状态，探索哺乳动物生理学 在这种状态下，并检查这种状态对癌症生长和化疗保护的影响。最后， 我们研究了不同物种包括非人类的torpor-regulating神经元的进化保守性 灵长类动物和人类组织，并检查是否可以在非人类灵长类动物中诱导类休眠状态， 为潜在的人类应用铺平了道路。这一建议是大胆和雄心勃勃的;然而， 拟议的项目包含明确定义和可行的实验，其结果有可能大大提高 推进，如果不是改变，我们对休眠，冬眠和恒温生物学的理解。创新和 这项工作的早期性质，沿着其推进医疗的潜力，使其非常适合于 新创新者奖。