Chilling time with synthetic torpor

合成麻木的冷却时间

• 批准号: BB/W007266/1
• 负责人: Anthony Pickering
• 金额: $ 55.18万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW007266%2F1
• 关键词: Chilling; time; synthetic; torpor

Torpor can be thought of as a short term hibernation. It is a protective physiological strategy adopted by many different species (including mice) to conserve energy during environmental challenges, such as exposure to low ambient temperature and/or food shortage and/or illness. Torpid animals actively and profoundly decrease their metabolic rate (by up to 90%) and temperature (to just above ambient temperature). Remarkably, animals emerge uneventfully from this state without incurring harm to themselves or their organ systems. In addition to creating resilience to decreased tissue delivery of oxygen and nutrients, torpor also modulates the immune system, enables tolerance of infection, promotes resistance to radiation and halts tumour growth. Because of these extraordinary characteristics, torpor has been studied for several decades, and even though some progress has been made in its understanding, the complex physiology triggering and regulating this state has been largely unknown. Since natural torpor is widespread across mammalian species (including some primates), it is reasonable to hypothesize that there are common brain circuits, present in all animals but active only in few of them. This suggests that the same neural circuit might be artificially activated in animals that do not show torpor (like rats or humans), allowing them to be induced to decrease their body temperature below the normal tightly regulated 37 degrees C. Recent advances have begun to identify the brain circuit responsible for torpor in the mouse hypothalamus in an area that is known to be involved in temperature regulation. Activation of particular neurons in this region can trigger Torpor without the need for an external motivation (like food shortage or cold ambient temperature). These neurons can be selectively targeted using genetic strategies to express engineered receptors for specific drugs or light sensitive proteins allowing 'synthetic torpor' to be switched on in mice at will, allowing us to undertake a detailed analysis of its physiology and neuronal circuit organisation. Almost all animals have day-night rhythms in their cellular and physiological processes whose synchronised co-ordination by molecular oscillators is important for health. There is evidence in hamsters that hibernation can cause these clocks to pause. It is not clear whether a similar phenomenon happens with torpor in mice - if it does happen then this could lead to de-synchronisation of the brain master clock and the body's local clocks (like happens with jet lag) which would be detrimental to the animal. We will test whether these clocks remain in synchrony during and after torpor (controlling for temperature) and how this is achieved. We will take a similar circuit dissection approach in rats to see whether we can produce 'synthetic torpor' in a non-hibernator species. This will start to define whether the same regulatory circuits are present in the rat hypothalamus and what prevents them from triggering torpor. In so doing we will learn about regulation and triggering of torpor and further identify whether this remarkable set of cellular and physiological adaptations which serve to protect the organism could one day be used in humans which could have a broad range of applications from space travel to healthcare.

Torpor可以被认为是一种短期的冬眠。这是许多不同物种（包括小鼠）在环境挑战（如暴露于低环境温度和/或食物短缺和/或疾病）时采用的一种保护性生理策略，以保存能量。冬眠的动物会积极而深刻地降低它们的代谢率（高达90%）和温度（略高于环境温度）。值得注意的是，动物们平静地从这种状态中出来，没有对自己或器官系统造成伤害。除了使组织对氧气和营养物质的输送减少产生弹性外，麻木还能调节免疫系统，使其能够耐受感染，增强对辐射的抵抗力，并阻止肿瘤的生长。由于这些非凡的特性，人们对昏睡的研究已经进行了几十年，尽管对它的理解已经取得了一些进展，但引发和调节这种状态的复杂生理机制在很大程度上还是未知的。由于自然麻木在哺乳动物物种（包括一些灵长类动物）中广泛存在，因此有理由假设存在共同的脑回路，这些回路存在于所有动物中，但仅在少数动物中活跃。这表明，同样的神经回路可能在没有表现出麻木的动物（如老鼠或人类）中被人为激活，允许它们被诱导将体温降低到正常严格控制的37摄氏度以下。最近的进展已经开始确定小鼠下丘脑中负责麻木的大脑回路，该区域已知与温度调节有关。该区域特定神经元的激活可以在不需要外部动机（如食物短缺或寒冷的环境温度）的情况下触发麻木。这些神经元可以选择性地使用遗传策略来表达特定药物或光敏蛋白的工程受体，从而使“合成麻木”在小鼠体内随意开启，从而使我们能够对其生理学和神经元回路组织进行详细分析。几乎所有动物的细胞和生理过程都有昼夜节律，分子振荡器的同步协调对健康很重要。有证据表明，仓鼠的冬眠会导致这些生物钟暂停。目前还不清楚小鼠是否也会出现类似的现象——如果真的发生了，那么这可能会导致大脑主时钟和身体局部时钟的不同步（就像时差一样），这对动物是有害的。我们将测试这些时钟是否在休眠期间和之后保持同步（控制温度），以及如何实现这一目标。我们将在老鼠身上采用类似的电路解剖方法，看看我们是否能在非冬眠物种身上产生“合成冬眠”。这将开始确定大鼠下丘脑中是否存在相同的调节回路，以及是什么阻止它们触发麻木。通过这样做，我们将了解麻木的调节和触发，并进一步确定这种用于保护生物体的非凡的细胞和生理适应是否有一天可以用于人类，这可能具有从太空旅行到医疗保健的广泛应用。