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

HPA 轴新兴功能动力学的机制研究

• 批准号: MR/N008936/1
• 负责人: Jamie Walker
• 金额: $ 110.84万
• 依托单位: UNIVERSITY OF EXETER
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN008936%2F1
• 关键词: mechanistic; investigation; into; emergent; functional

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.

有节奏的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础。有些身体节奏对我们来说非常明显，比如我们的心脏跳动和我们每天的睡眠-觉醒周期，但体内绝大多数的节奏过程并不那么明显。当这些振荡以某种方式改变或被破坏时，这可能对我们的福祉产生重大影响。这方面的例子包括大脑活动中出现异常节律，这可以在患有癫痫或帕金森病的患者中看到。激素信号由许多激素的节律性活动控制，这些激素遵循每日周期。一个很好的例子是至关重要的类固醇激素皮质醇，这是最重要的激素之一，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）期间较低，但在清晨增加，为身体的日常活动做好准备。除了这种每日节律外，我们现在还知道，皮质醇水平实际上在一天中每隔一个小时左右就会发生更快的波动，早晨的波动更大。最近的研究表明，皮质醇波动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炎症或恶性疾病的患者通常仍然暴露于恒定水平的强效，长效，合成类固醇。这种传递模式是在皮质醇脉动的重要性变得清晰之前发展起来的，并且可能会限制治疗的效果，以及导致与长期使用合成类固醇相关的非常高水平的副作用。暴露于早期生活压力或过大或长时间的压力会大大破坏皮质醇振荡。这反过来又对控制我们行为的大脑区域产生了重大影响，并增加了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迅速增加的特征，我们必须更深入地了解身体如何调节皮质醇产生的动态模式。在我的研究中，我采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影响？心律失常可以“正常化”吗？提供这些问题的答案不仅会改变我们对健康和疾病中皮质醇信号的理解，而且对于在临床上开发新型治疗策略也很重要，这些策略考虑到了向接受长期类固醇治疗的患者提供激素的时机。

项目成果

Modelling the dynamic interaction of systemic inflammation and the hypothalamic-pituitary-adrenal (HPA) axis during and after cardiac surgery.

• DOI: 10.1098/rsif.2021.0925
• 发表时间: 2022-04
• 期刊: Journal of the Royal Society, Interface

Activation and expression of endogenous CREB-regulated transcription coactivators (CRTC) 1, 2 and 3 in the rat adrenal gland.

• DOI: 10.1111/jne.12920
• 发表时间: 2021-01
• 期刊: Journal of neuroendocrinology
• 影响因子: 3.2
• 作者: Smith LIF;Zhao Z;Walker J;Lightman S;Spiga F
• 通讯作者: Spiga F

Circadian distribution of epileptiform discharges in epilepsy: Candidate mechanisms of variability.

• DOI: 10.1371/journal.pcbi.1010508
• 发表时间: 2023-10
• 期刊: PLoS computational biology
• 影响因子: 4.3

Dynamic responses of the adrenal steroidogenic regulatory network

肾上腺类固醇生成调节网络的动态反应

• DOI: 10.1530/ey.15.8.4
• 发表时间: 2018
• 期刊: Yearbook of Paediatric Endocrinology
• 作者: F S

Heterogeneity of Calcium Responses to Secretagogues in Corticotrophs From Male Rats.

• DOI: 10.1210/en.2017-00107
• 发表时间: 2017-06-01
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Romanò N;McClafferty H;Walker JJ;Le Tissier P;Shipston MJ
• 通讯作者: Shipston MJ