Investigation of the role of calcium in circadian rhythms

几乎我们生理和行为的所有方面都显示出24小时的变化，由生物钟驱动，生物钟可以在我们身体的每个细胞中找到。在哺乳动物中，主时钟存在于大脑中，它从眼睛接收光信息并将其传递到身体的其他组织，以使生物过程与24小时环境光暗周期同步。由生物钟调节的过程的例子包括睡眠-觉醒周期，激素分泌和体温的调节，以及更复杂的过程，如认知和记忆形成。鉴于生物钟在调节大量生理过程中的重要性，生物钟的破坏导致从糖尿病到情绪障碍的各种疾病也就不足为奇了。虽然在识别参与昼夜节律产生的关键蛋白质方面取得了很大进展，但我们对细胞信号传导过程如何在分子水平上影响昼夜节律的理解远远落后。环境信息，如一天中的时间是通过信号传导机制传递给分子钟的，对这些机制的理解是开发可用于靶向生物钟的药物的关键，在此应用中，我们建议探索钙的作用，钙可以说是最普遍存在的细胞信号信使，在调节昼夜节律。钙信号在调节基因如何以及何时响应环境刺激而开启和关闭方面起着重要作用，几乎所有系统都包括心脏和大脑。我们的初步工作表明，钙很可能在昼夜节律的基础调节网络中发挥根本性的重要作用，并延伸到所有细胞的生物节律。我们建议在这些发现的基础上，对钙的作用及其调节核心分子钟的信号通路进行详细的研究。

Virtually all aspects of our physiology and behaviour display 24-hour variations, driven by a circadian clock, which can be found every cell of our body. In mammals, the master clock is present in the brain, which receives light information from the eye and relays it to other tissues in the body to synchronise biological processes with the 24h environmental light-dark cycle. Examples of processes regulated by the clock include the sleep-wake cycle, the regulation of hormone secretion and body temperature and also more complex processes such as cognition and memory formation. Given the importance of clock in regulating large swathes of physiological processes, it's not surprising that disruption of the circadian clock leads to various disorders ranging from diabetes to mood disorders. Whilst there has been great progress in the identification of key proteins involved in the generation of circadian rhythms, we are much further behind in our understanding of how cellular signalling processes influence the circadian clock at the molecular level. Environmental information, such as the time of day are communicated to the molecular clock by signalling mechanisms and an understanding of these mechanisms holds the key to developing drugs that may be used to target the clock.In this application we propose to explore the role of calcium, arguably the most ubiquitous cellular signalling messenger, in regulating circadian rhythms. Calcium signalling plays a major role in regulating how and when genes are turned on and off in response to environmental stimuli in nearly all systems including the heart and brain. Our preliminary work shows that calcium is likely to play a fundamentally important role in the regulatory networks underlying circadian rhythms, and by extension, biological rhythms in all cells. We propose to build upon these findings and conduct a detailed investigation on the role of calcium and the signalling pathways by which it modulates the core molecular clock.