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.

该项目旨在了解寒冷温度调节基因和行为的分子机制。为了应对严重的环境条件，例如冬季或食物短缺时的寒冷温度，许多哺乳动物采用了一种非凡的行为，称为Torpor。在这里，动物进入了新陈代谢的降低状态，伴随着其体温急剧下降。一系列长时间的Torpor被称为冬眠。尽管Torpor对动物生物学的重要性，但迄今为止，我们不理解控制进入，维护和退出该州的分子机制，但是这种知识将为急诊医学，寿命，寿命，寿命，寿命，寿命，长寿，寿命的进步提供基础，和太空旅行。我们最近确定了冷却和昼夜节律之间的联系，这可能解释了Torpor的一些最基本方面。昼夜节律是一个古老的高度保守的时间，保持所有生命固有的机制。昼夜节律的时钟几乎使细胞和生物生理的所有方面与地球的24小时和夜间周期保持一致。将时钟调整到不断变化的环境的能力对健康至关重要，我们大多数人都以“ Jetlag”的形式经历了麦芽调整的时钟的后果。温度是昼夜节律时钟至关重要的时间，并且如何解释该信号对时钟基因的影响很大程度上是未知的。我们发现，在手术过程中，患者经历了将人心脏细胞冷却至低温，对此产生了深远的影响。染色体的结构。这导致基因的戏剧性激活对昼夜节律进行负调节，从而停止或“冻结”其节奏性。重新传输细胞会重新激活节奏性，并有效地引起时钟的重置。我们在人类细胞模型中进行的这些观察结果与小型哺乳动物的Torpor之间存在显着相似之处。当动物进入Torpor并重置昼夜节律时，已经激活了相同的基因，这对于从Torpor出口至关重要。这些相似之处提供了一个独特的机会，可以解决控制昼夜节律和torpor的基本机制。我们使用培养的人类细胞的冷却和恢复方法为我们提供了一种简单但有效的可控程序，以揭示改变染色体结构的分子机制，从而改变了染色体的结构，从而改变了染色体的结构。激活和失活的时钟基因。在此提案中，我们将使用最新的生化和显微镜方法来表征以前所未有的分辨率以染色体结构的变化，并阐明该如何调节和重置细胞时钟。然后，我们可以使用相同的方法来了解这些机制如何控制和重新配置小鼠在Torpor中的细胞。定义重新配置染色体结构在细胞时钟调节中发挥作用的作用是对基于细胞时间保留的力学及其在TORPOR等生物学过程中的作用的理解的基础。虽然我们无法进入Torpor，但对这些机制的理解可能会提供诱导人类中的状态的策略。这将在医学中开放巨大的新应用，尤其是用于治疗创伤患者以防止组织损害的治疗，并可能有助于储存移植器官的储存。此外，Torpor作为工具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，以使人类能够在持续时间长的空间旅行中生存。