A mechanistic investigation into the emergent functional dynamics of the HPA axis

有节奏或振荡的活动在自然界中无处不在，对我们自己的生理来说绝对是基本的。有些身体节律对我们来说是非常明显的，比如我们的心跳和我们每天的睡眠-觉醒周期，但体内绝大多数的节律过程并不那么明显。当这些振荡以某种方式改变或被扰乱时，这可能会对我们的福祉产生重大影响。这方面的例子包括癫痫或帕金森氏症患者的大脑活动出现异常节律。荷尔蒙信号由节律活动控制，许多荷尔蒙遵循每日周期。一个很好的例子是至关重要的类固醇激素皮质醇，它是最重要的荷尔蒙之一，使我们能够对压力情况做出快速和适当的反应。皮质醇水平在休息(睡眠)期间很低，但在清晨会升高，为身体的日常活动做准备。除了这种日常节律，我们现在知道皮质醇水平实际上在一天中每小时左右振荡得更快，更大的脉冲发生在早上。最近的研究表明，皮质醇振荡对健康的身体功能至关重要，因为它们控制着许多重要基因的活动，并确保身体处于应对压力的理想状态。值得注意的是，接受激素替代或类固醇治疗的炎症性或恶性疾病患者通常仍然暴露在持续水平的有效、长效、合成类固醇之下。这种给药模式是在皮质醇脉动性的重要性变得清晰之前就发展起来的，可能会限制治疗效果，并导致长期使用合成类固醇的副作用水平很高。暴露在早期应激或过大或过长的应激状态下可以实质上扰乱皮质醇的振荡。这反过来又会对大脑中控制我们行为的区域产生重大影响，并增加对许多疾病的易感性。鉴于压力和与压力相关的疾病是现代社会快速增长的特征，我们必须更深入地了解身体是如何调节皮质醇产生的动态模式的。在我的研究中，我使用数学建模方法结合最先进的实验技术来解决一些关键问题：皮质醇节律是如何产生的？身体发生了什么变化，导致了我们在疾病中看到的异常节律？这些被打乱的节奏对我们的生理和心理健康有什么后果？不正常的节律能被“正常化”吗？提供这些问题的答案不仅将改变我们对皮质醇信号在健康和疾病中的理解，而且对于在临床上开发新的治疗策略也很重要，这些策略将考虑到向接受长期类固醇治疗的患者提供激素的时机。

Rhythmic or oscillating activity is everywhere in nature and is absolutely fundamental to our own physiology. Some bodily rhythms are very obvious to us, such as the beating of our heart and our daily sleep-wake cycle, but the vast majority of rhythmic processes inside the body are not so obvious. When these oscillations change in some way or become disrupted, this can have major consequences for our well-being. Examples of this include the emergence of abnormal rhythms in brain activity that can be seen in patients suffering from epilepsy or Parkinson's disease.Hormonal signalling is governed by rhythmic activity with many hormones following a daily cycle. A good example of this is the vital steroid hormone cortisol, one of the most important hormones that enables us to respond rapidly and appropriately to stressful situations. Cortisol levels are low during periods of rest (sleep) but increase early in the morning to prepare the body for daily activity. In addition to this daily rhythm, we now know that levels of cortisol are actually oscillating much more rapidly every hour or so throughout the day, with larger pulses occurring in the morning.Recent research has demonstrated that cortisol oscillations are critical for healthy bodily function as they control the activity of many important genes and ensure that the body is in an ideal state to respond to stress. Remarkably, patients undergoing hormone replacement or steroid therapy for inflammatory or malignant disease are typically still being exposed to constant levels of potent, long-acting, synthetic steroids. This pattern of delivery was developed before the importance of cortisol pulsatility became clear, and may well limit efficacy of treatment as well as contribute to the very high levels of side effects associated with the long-term use of synthetic steroids.Exposure to early-life stress or excessively large or prolonged periods of stress can substantially disrupt cortisol oscillations. This in turn has major consequences for regions of the brain that control our behaviour and also increases susceptibility to many diseases. Given that stress and stress-related illness are rapidly-increasing features of modern society, it is crucial that we gain a deeper understanding of how the body regulates the dynamic pattern of cortisol production. In my research, I am employing mathematical modelling approaches in combination with state-of-the-art experimental technologies to address a number of key questions: How are cortisol rhythms generated? What changes occur in the body that lead to the abnormal rhythms we see in disease? What consequences do these disrupted rhythms have for our physiological and mental well-being? Can abnormal rhythms be "normalised"? Providing answers to these questions will not only transform our understanding of cortisol signalling in both health and disease, but will also be important for developing novel treatment strategies in the clinic that take into account timing of hormone delivery to patients undergoing long-term steroid therapy.