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.

项目总监/首席研究员（最后、第一、中间）：Hrvatin、Sinisa 项目概要： 地球上的生命已经进化出令人着迷的适应能力，例如麻木和冬眠，以在极端环境下生存 环境。这些非凡的适应的特点是生理功能严重下降 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最迷人的谜团之一 生物学，对生物学的理解可能对人类医学产生深远的影响。正在调查，对于 例如，适应性调节新陈代谢的机制可以提供新的调节方法 人体能量平衡和治疗代谢疾病。诱导的体温过低和代谢低下状态可能 减缓疾病进展，例如癌症的生长。使细胞和器官处于麻木状态的途径 为了在缺氧和低温应激下生存而冬眠也可以用来促进细胞存活 在外伤、中风、心脏骤停、化疗甚至神经退行性疾病期间。物种之中自然 能够进入这些状态的是实验室小鼠。将小鼠置于没有食物的环境中会引发麻木状态 - 一种以核心体温、运动和代谢率大幅降低为特征的行为， 持续几个小时。最近，采用新颖的转基因工具和测序方法，我们检查了 这种复杂的行为，并发现小鼠的麻木状态是由大脑中不同的神经元群调节的 下丘脑。抑制这些神经元可以防止自然麻木，刺激它们可以快速降低新陈代谢 率和体温，引起类似麻木的状态。这一发现为未来奠定了基础 探索调节麻木和冬眠的机制，首次实现基因获取 监控、发起、操纵和研究这些行为。在此提案中，我们调查了未解答的关键问题 麻木和冬眠领域的问题并探索诱导冬眠的潜在应用 癌症生物学领域的国家。具体来说，我们检查调节身体功能下降的神经元回路。 温度和代谢率，并探索循环因素在诱导这种生物体范围状态中的作用。 我们开创了一种新方法来诱导小鼠进入长期冬眠状态，探索哺乳动物的生理学 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， 我们研究了跨物种（包括非人类）的麻木调节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似麻木的状态， 为潜在的人类应用铺平道路。这个提议是大胆而雄心勃勃的；然而，每个 拟议的项目包含明确定义和可行的实验，其结果有可能极大地 推进（如果不是改变的话）我们对麻木、冬眠和恒温生物学的理解。创新和 这项工作的早期性质及其促进医学治疗的潜力，使其非常适合 新创新奖。