The pituitary corticotroph: an organizing centre for oscillatory activity of the HPA axis?

垂体促肾上腺皮质激素：HPA 轴振荡活动的组织中心？

• 批准号: MR/J013811/1
• 负责人: Jamie Walker
• 金额: $ 47.39万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FJ013811%2F1
• 关键词: pituitary; corticotroph; organizing; centre; oscillatory

Rhythms are everywhere in nature, and nearly all hormonal systems in our bodies follow a daily cycle. A good example of this is the hypothalamic-pituitary-adrenal (HPA) axis, which regulates the secretion of the vital hormone cortisol, and is the major hormonal system in mammals that provides a rapid response and defence against stress. Cortisol levels are low during periods of resting (sleep) and rise early in the morning to prepare an individual for daily activity.However, we now know that this hormone is actually secreted in pulses, or short bursts, every hour or so throughout the day, with larger pulses during the morning, making up the general circadian trend. There is now significant evidence that in order for tissues in the body to function 'optimally', oscillating levels of cortisol are essential.Despite this, patients undergoing both hormone replacement and steroid therapy for inflammatory or malignant disease are typically exposed to constant levels of long-acting synthetic steroids. This pattern of delivery was developed before we understood the importance of cortisol pulsatility, 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. Moreover, we also now know that the cortisol rhythm becomes disrupted in different physiological and pathological conditions. Good examples of this are the disruptions to the rhythm that are associated with ageing and prolonged stress.Given that stress-related illness is a rapidly increasing feature of our society, and that aging is a major risk factor for cognitive decline, decreased immune response and frailty, it is very important that we understand the biological mechanisms that govern the body's endogenous production of cortisol; and also how these cycling levels of hormone help to optimise the body's response to environmental influences and to maintain normal internal regulatory processes. Given the complexity of the HPA axis, mathematical models provide a powerful tool with which to appropriately identify these biological mechanisms. By using this approach, we have recently identified a potential network in the body that regulates the pulsatile secretion of cortisol. This is particularly exciting because, now that we understand where this rhythm originates from, we can begin to systematically probe the key mechanisms that are important for maintaining a 'normal' rhythm. This, in turn, will help us to understand how and why the rhythm changes in ageing and disease, and how these changes cause, or protect us from pathological consequences.

节奏在自然界无处不在，我们体内几乎所有的荷尔蒙系统都遵循着每日的循环。一个很好的例子是下丘脑-垂体-肾上腺轴（HPA），它调节重要激素皮质醇的分泌，是哺乳动物的主要激素系统，提供快速反应和防御压力。在休息（睡眠）和早起为日常活动做准备时，皮质醇水平较低。然而，我们现在知道，这种激素实际上是在一天中每小时左右以脉冲或短脉冲的形式分泌的，早晨的脉冲更大，构成了总体的昼夜节律趋势。现在有重要的证据表明，为了使身体组织“最佳”运作，皮质醇水平的波动是必不可少的。尽管如此，接受激素替代和类固醇治疗炎症或恶性疾病的患者通常暴露于恒定水平的长效合成类固醇。这种给药模式是在我们了解皮质醇搏动的重要性之前发展起来的，可能会限制治疗的效果，并导致与长期使用合成类固醇相关的非常高的副作用。此外，我们现在也知道皮质醇节律在不同的生理和病理条件下会被打乱。这方面的一个很好的例子是与衰老和长期压力相关的节奏中断。鉴于与压力相关的疾病在我们的社会中是一个迅速增加的特征，而衰老是认知能力下降、免疫反应下降和身体虚弱的主要风险因素，我们了解控制身体内源性皮质醇产生的生物机制是非常重要的；以及这些激素的循环水平如何帮助优化身体对环境影响的反应，并维持正常的内部调节过程。考虑到HPA轴的复杂性，数学模型提供了一个强大的工具，可以适当地识别这些生物机制。通过使用这种方法，我们最近确定了体内调节皮质醇脉动分泌的潜在网络。这是特别令人兴奋的，因为现在我们了解了这种节奏的起源，我们可以开始系统地探索维持“正常”节奏的重要关键机制。反过来，这将帮助我们理解在衰老和疾病中节奏变化的方式和原因，以及这些变化是如何导致或保护我们免受病理后果的。

项目成果

Ultradian corticosterone secretion is maintained in the absence of circadian cues.

在没有昼夜节律提示的情况下，超昼夜皮质酮分泌得以维持。

• DOI: 10.1111/j.1460-9568.2012.08213.x
• 发表时间: 2012
• 期刊: The European journal of neuroscience
• 作者: Waite EJ

Dynamic pituitary-adrenal interactions in response to cardiac surgery.

• DOI: 10.1097/ccm.0000000000000773
• 发表时间: 2015-04
• 期刊: Critical care medicine
• 影响因子: 8.8
• 作者: Gibbison B;Spiga F;Walker JJ;Russell GM;Stevenson K;Kershaw Y;Zhao Z;Henley D;Angelini GD;Lightman SL
• 通讯作者: Lightman SL

Computational Neuroendocrinology

计算神经内分泌学

• DOI: 10.1002/9781119159438.ch8
• 发表时间: 2016
• 作者: Terry J

Rapid intra-adrenal feedback regulation of glucocorticoid synthesis.

• DOI: 10.1098/rsif.2014.0875
• 发表时间: 2015-01-06
• 期刊: Journal of the Royal Society, Interface
• 作者: Walker JJ;Spiga F;Gupta R;Zhao Z;Lightman SL;Terry JR
• 通讯作者: Terry JR