Characterising the mechanisms through which the HPA axis maintains homeostasis in health and disease: A multiscale, multidisciplinary approach

描述 HPA 轴维持健康和疾病稳态的机制：多尺度、多学科方法

• 批准号: MR/J008893/1
• 负责人: Stafford Lightman
• 金额: $ 277.11万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 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%2FJ008893%2F1
• 关键词: Characterising; mechanisms; through; HPA; axis

The hypothalamic-pituitary-adrenal (HPA) axis dynamically regulates levels of the stress hormone cortisol. This axis is critical for the maintenance of homeostasis, and is the major hormonal system that provides a rapid response and defence against acute stress. Unfortunately, when exposure to stress becomes prolonged, the response of the HPA can become maladaptive and predispose an individual to illness - particularly cardiovascular, metabolic and cognitive dysfunction. There is now an increasing body of evidence that in order to achieve optimal function - from cellular response through to behaviour - oscillating levels of cortisol are required. In complete contrast to the natural state, patients undergoing both hormone replacement and glucocorticoid 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 glucocorticoid rhythmicity 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 glucocorticoids. It is therefore very important that we now re-evaluate the therapeutic application of glucocorticoids and to do so it is crucial that we understand the biological mechanisms governing the body's endogenous production of these steroids and further how these cycling levels of hormones help to optimise the body's response to environmental influences and to maintain normal internal regulatory processes. To address these questions, the approach we will pursue is to integrate data obtained from cellular, tissue and whole systems studies through the development of a suite of computational and mathematical models .Using these models we shall probe the data for the likely generators of our experimental observations and to guide the development of new experiments that can validate the predictions of our mathematical models. Given the complexity of the HPA-axis, where dynamic patterns of activity emerge from interactions across many spatial and temporal scales within the system, mathematical models provide a natural suite of tools with which to interrogate our data. Ultimately we plan to fully integrate our approaches through the development of a hybrid testing approach. This means that we couple part of the system that we wish to study experimentally, with a computational model of the rest of the system. This will enable us to study the specific subcomponent as if it remained part of the whole system. Such an approach will be crucial to appropriately identify the biological mechanisms that give rise to disrupted rhythmicity associated with disease and ageing, since the behaviour of a component of a system in isolation may not be reflective of its behaviour when integrated within the whole system.

下丘脑-垂体-肾上腺(HPA)轴动态调节应激激素皮质醇的水平。这个轴对维持体内平衡至关重要，是提供快速反应和防御急性应激的主要激素系统。不幸的是，当长时间暴露在压力下时，HPA的反应可能会变得不适应，使个人容易患上疾病--特别是心血管、代谢和认知功能障碍。现在有越来越多的证据表明，为了实现从细胞反应到行为的最佳功能，皮质醇水平的波动是必需的。与自然状态完全相反的是，对于炎症性或恶性疾病，同时接受激素替代和糖皮质激素治疗的患者通常会接触到持续水平的长效合成类固醇。这种给药模式是在我们了解糖皮质激素节律性的重要性之前开发出来的，可能会限制治疗效果，并导致长期使用合成糖皮质激素的副作用水平很高。因此，我们现在重新评估糖皮质激素的治疗应用是非常重要的，为此，我们必须了解控制人体内源性类固醇产生的生物学机制，以及这些激素的循环水平如何帮助优化人体对环境影响的反应，并维持正常的内部调节过程。为了解决这些问题，我们将采取的方法是通过开发一套计算和数学模型来整合从细胞、组织和整个系统研究中获得的数据。使用这些模型，我们将探索实验观察的可能生成器的数据，并指导新实验的发展，这些实验可以验证我们的数学模型的预测。考虑到HPA轴的复杂性，其中动态的活动模式出现在系统内许多空间和时间尺度上的交互作用中，数学模型提供了一套自然的工具来询问我们的数据。最终，我们计划通过开发混合测试方法来完全整合我们的方法。这意味着我们将我们希望通过实验研究的系统的一部分与系统其余部分的计算模型相耦合。这将使我们能够研究特定的子组件，就像它仍然是整个系统的一部分一样。这种方法对于适当确定引起疾病和衰老相关节律紊乱的生物机制至关重要，因为孤立的系统组成部分的行为可能不能反映其在融入整个系统时的行为。

项目成果

The Role of Hippocampal NMDA Receptors in Long-Term Emotional Responses following Muscarinic Receptor Activation.

• DOI: 10.1371/journal.pone.0147293
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Hoeller AA;Costa AP;Bicca MA;Matheus FC;Lach G;Spiga F;Lightman SL;Walz R;Collingridge GL;Bortolotto ZA;de Lima TC
• 通讯作者: de Lima TC

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

Co-culture of monocytes and zona fasciculata adrenal cells: An in vitro model to study the immune-adrenal cross-talk.

• DOI: 10.1016/j.mce.2021.111195
• 发表时间: 2021-04-15
• 期刊: Molecular and cellular endocrinology
• 影响因子: 4.1
• 作者: Fudulu DP;Horn G;Hazell G;Lefrançois-Martinez AM;Martinez A;Angelini GD;Lightman SL;Spiga F
• 通讯作者: Spiga F

Role of glucocorticoid negative feedback in the regulation of HPA axis pulsatility.

• DOI: 10.1080/10253890.2018.1470238
• 发表时间: 2018-09
• 期刊: Stress (Amsterdam, Netherlands)
• 作者: Gjerstad JK;Lightman SL;Spiga F
• 通讯作者: Spiga F

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