Characterising the feedback control mechanisms of the glucocorticoid receptor within the adrenal steroidogenic regulatory network

近几十年来，现代生物医学问题变得非常复杂。最近的科学发现表明，从动态的角度更好地理解我们的身体，其中一些生理过程一直在积极地变化和适应。事实上，许多健康失调现在被更好地理解为某种“动态平衡”的破坏，而不是正常生理的“静态画面”。正因为如此，除了来自分子生物学和生物化学的强大实验技术之外，从数学、物理学和计算机科学中借鉴的新工具对于理解这些动力学和理解导致疾病的破坏机制是必要的。下丘脑-垂体-肾上腺（HPA）轴的动态也不例外。这种体内平衡系统通过控制应激激素的动态分泌来控制我们的身体对压力的反应能力，应激激素在肾上腺中迅速合成。这发生在脑下垂体分泌的另一种激素的刺激下。在正常的生理条件下，这两种激素水平在白天几乎完全同步波动。然而，在压力和其他病理条件下，这种行为可能会改变，并被“解离动态”状态所取代，在这种状态下，这些激素的波动不再同步。我们目前对潜在的调节机制以及它们的破坏如何导致疾病缺乏了解，这阻碍了临床医生为越来越多患有压力相关疾病的患者提供更好的治疗方法。最近的研究工作集中在了解肾上腺内控制垂体信号后应激激素合成的调节机制。在此期间，我将建立这些机制的数学模型，并预测在疾病期间激素动力学是如何被破坏的。事实上，我目前的数学模型表明，这个网络的一个组成部分可能作为一个组织“枢纽”，整合这些激素信号，并负责它们的分离。为了探索这一点，我将开发一个数学框架来预测激素信号如何控制类固醇生成相关因子的表达，包括基因调控的合理生物物理机制。然后，我将进行实验来验证我的模型预测，并展示这些激素如何调节类固醇基因的表达。最后，我将把我的基因调控模型整合到更大的、多尺度的肾上腺和下丘脑轴模型中，并用它们来预测一些实验、药物治疗以及生理和病理条件。长期目标是了解控制身体内源性应激激素产生的生物学机制，这样我们就可以为患有肾上腺功能不全和压力相关疾病的患者开发更好的治疗方法。

Modern problems in biomedicine have become very complex in the last decades. Recent scientific findings demonstrate that our bodies are better understood from a dynamic perspective, where several physiological processes are actively changing - and adapting - all the time. In fact, many health disorders are now better understood as disruptions of a certain "dynamic equilibrium", rather than as "static pictures" of normal physiology. Because of this, in addition to the powerful experimental techniques from molecular biology and biochemistry, novel tools borrowed from mathematics, physics and computer science are necessary to understand these dynamics and make sense of the disrupting mechanisms that lead to disease.The dynamics of the Hypothalamic-Pituitary-Adrenal (HPA) axis is no exception. This homeostatic system controls our bodies' ability to respond to stress through the controlled, dynamic secretion of stress hormones that are rapidly synthesised in the adrenal glands. This occurs following stimuli from another hormone secreted by the pituitary gland. In normal, physiological conditions, both hormone levels fluctuate during the day in almost perfect synchrony. However, this behaviour can become altered during stress and in other pathological conditions, and is replaced by a "dissociated dynamic" state where fluctuations of these hormones are not synchronised anymore. Our current lack of understanding of the underlying regulatory mechanisms, and how their disruption leads to disease, is preventing clinicians delivering better treatments to a growing number of patients suffering from stress-related illness.Recent research efforts have focused on understanding the regulatory mechanisms within the adrenal gland that control the synthesis of stress hormones following signals from the pituitary. During this fellowship, I will develop mathematical models of these mechanisms and predict how hormone dynamics is disrupted during disease. In fact, my current mathematical models suggest that a component of this network may act as an organising "hub" that integrates these hormone signals and is responsible for their dissociation.To explore this, I will develop a mathematical framework to predict how hormone signals may control the expression of factors involved in steroidogenesis, including plausible biophysical mechanisms of gene regulation. Then, I will carry out experiments to test my model predictions and show how these hormones modulate the expression of steroidogenic genes. Lastly, I will integrate my models of gene regulation into larger, multiscale models of the adrenal gland and the HPA axis, and use them to generate predictions about a number of experiments, drug treatments, and physiological and pathological conditions. The long-term goal is to understand the biological mechanisms that govern the body's endogenous production of stress hormones, so that we can develop better therapies for patients suffering from adrenal insufficiency and stress-related disorders.