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

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压力的主要激素系统。不幸的是，当长期暴露在压力下时，HPA的反应会变得不适应，并使个体容易患病——尤其是心血管、代谢和认知功能障碍。现在有越来越多的证据表明，为了实现最佳功能——从细胞反应到行为——皮质醇水平的波动是必需的。与自然状态完全相反，因炎症或恶性疾病而接受激素替代和糖皮质激素治疗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糖皮质激素节律性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糖皮质激素相关的非常高的副作用。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，要做到这一点，我们必须了解控制身体内源性类固醇生产的生物机制，以及这些激素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。为了解决这些问题，我们将采用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，我们将为实验观察的可能产生者探索数据，并指导新实验的发展，以验证我们的数学模型的预测。考虑到hpa轴的复杂性，动态活动模式从系统内许多空间和时间尺度的相互作用中出现，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集成我们的方法。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结合起来。这将使我们能够研究特定的子组件，就好像它仍然是整个系统的一部分一样。这种方法对于适当查明导致与疾病和衰老有关的节律性紊乱的生物机制至关重要，因为系统中孤立的一个组成部分的行为可能不能反映其在整个系统中整合时的行为。

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.