The cold-responsive circadian gene regulatory landscape and its relevance to torpor

寒冷反应昼夜节律基因调控景观及其与冬眠的相关性

• 批准号: BB/Y005848/1
• 负责人: Andre Furger
• 金额: $ 132.46万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FY005848%2F1
• 关键词: cold; responsive; circadian; gene; regulatory

This project aims to understand the molecular mechanisms by which cold temperatures regulate genes and behaviour. In response to severe environmental conditions such as cold temperatures during winter or at times of food shortage, many mammals adopt a remarkable behaviour known as torpor. Here, animals enter a state of reduced metabolism, and this is accompanied by a drastic drop in their body temperature. A series of prolonged bouts of torpor is referred to as hibernation. Despite the importance of torpor to animal biology, to date, we do not understand the molecular mechanisms that control the entry, maintenance, and exit from this state, but such knowledge would provide the substrate for paradigm-shifting advances in emergency medicine, longevity, and space travel. We have recently identified links between cooling and the circadian clock that may explain some of the most fundamental aspects of torpor. The circadian clock is an ancient highly conserved time keeping mechanism inherent to all life. The circadian clock aligns almost all aspects of cellular and organism physiology to the earth's 24h day and night cycle. The ability to adjust the clock to a changing environment is of fundamental importance to health and most of us have experienced the consequences of a mal-adjusted clock in the form of "jetlag". Temperature is a crucial time cue to the circadian clock, and how this signal is interpreted to impact on clock genes is largely unknown.We discovered that cooling human heart cells to low temperatures, as experienced by patients during surgical procedures, has a profound impact on the architecture of the chromosomes. This results in the dramatic activation of genes that negatively regulate the circadian clock and thus stop or "freeze" its rhythmicity. Rewarming cells reactivates rhythmicity and effectively causes the resetting of the clock. There are remarkable similarities between these observations we made in the human cell model and torpor in small mammals. The same genes are activated when animals enter torpor and resetting of the circadian clock has been proposed to be critical for the exit from torpor. These parallels offer a unique opportunity to address the fundamental mechanisms that control both circadian rhythms and torpor.Our cooling and rewarming approach using cultured human cells provides us with a simple but effective controllable procedure to unravel the molecular mechanisms that change the structure of chromosomes and thus activate and deactivate clock genes. In this proposal we will use the very latest biochemical and microscopy approaches to characterise the changes to the architecture of the chromosomes at unprecedented resolution and elucidate how this regulates and resets the cellular clock. We can then use the same methodology to understand how these mechanisms also govern and reconfigure the cells of mice in torpor. Defining the role that the reconfiguration of chromosomal architecture plays in the regulation of the cellular clock is fundamental to the understanding of the mechanics that underpin cellular time keeping, and its role in biological processes such as in torpor. Whilst we cannot enter torpor, understanding of these mechanisms may provide strategies to induce torpor like states in humans. This would open tremendous new applications in medicine in particular for the treatment of trauma patients to prevent tissue damage and may help to prologue the storage of transplant organs. In addition, torpor as a tool would provide solutions to many challenges including muscle and bone loss, and radiation exposure that have to be overcome to enable humans to survive long duration space travel.

该项目旨在了解低温调节基因和行为的分子机制。为了应对恶劣的环境条件，如冬季的低温或食物短缺时，许多哺乳动物采取了一种被称为“冬眠”的非凡行为。在这里，动物进入一种新陈代谢降低的状态，这伴随着体温的急剧下降。一连串长时间的昏睡被称为冬眠。尽管冬眠对动物生物学很重要，但到目前为止，我们还不了解控制这种状态进入、维持和退出的分子机制，但这些知识将为急诊医学、长寿和太空旅行的范式转变提供基础。我们最近发现了降温和生物钟之间的联系，这可能解释了麻木的一些最基本的方面。生物钟是所有生命固有的一种古老的高度保守的时间保持机制。生物钟几乎使细胞和有机体生理的所有方面与地球24小时昼夜循环一致。调整生物钟以适应环境变化的能力对健康至关重要，我们大多数人都经历过生物钟调整不当的后果，即“时差”。温度是生物钟的关键时间线索，而这个信号是如何被解释为影响生物钟基因的，这在很大程度上是未知的。我们发现，将人类心脏细胞冷却到低温，就像病人在手术过程中所经历的那样，对染色体的结构有深远的影响。这导致对生物钟进行负面调节的基因急剧激活，从而停止或“冻结”其节律性。重新升温的细胞重新激活了节律性，并有效地导致了生物钟的重置。我们在人类细胞模型中所做的观察和在小型哺乳动物中所做的观察有显著的相似之处。当动物进入昏睡状态时，同样的基因被激活，生物钟的重置被认为是脱离昏睡状态的关键。这些相似之处提供了一个独特的机会来解决控制昼夜节律和麻木的基本机制。我们使用培养的人类细胞进行冷却和再加热的方法为我们提供了一个简单但有效的可控过程，以揭示改变染色体结构的分子机制，从而激活和停用时钟基因。在本提案中，我们将使用最新的生化和显微镜方法以前所未有的分辨率描述染色体结构的变化，并阐明这是如何调节和重置细胞时钟的。然后，我们可以用同样的方法来理解这些机制是如何控制和重新配置处于休眠状态的小鼠细胞的。定义染色体结构重构在细胞时钟调节中的作用，对于理解支撑细胞计时的机制及其在诸如睡眠等生物过程中的作用至关重要。虽然我们不能进入麻木状态，但对这些机制的理解可能会提供在人类中诱导类似麻木状态的策略。这将在医学上开辟巨大的新应用，特别是对创伤患者的治疗，以防止组织损伤，并可能有助于促进移植器官的储存。此外，作为一种工具，麻木将为许多挑战提供解决方案，包括肌肉和骨质流失，以及必须克服的辐射暴露，以使人类能够在长时间的太空旅行中生存。