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

在过去的几十年里，生物医学中的现代问题变得非常复杂。最近的科学发现表明，我们的身体从动态的角度得到了更好的理解，其中几个生理过程一直在积极变化和适应。事实上，现在人们更好地将许多健康障碍理解为某种“动态平衡”的破坏，而不是正常生理的“静态图景”。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外，还需要借用数学、物理和计算机科学的新工具来理解这些动力学，并理解导致疾病的破坏机制。下丘脑-垂体-肾上腺(HPA)轴的动力学也不例外。这种体内平衡系统通过受控的、动态的应激激素分泌来控制我们身体对压力的反应能力，应激激素在肾上腺中迅速合成。这是在脑下垂体分泌的另一种荷尔蒙刺激下发生的。在正常的生理条件下，这两种激素水平在一天中几乎完全同步地波动。然而，在压力和其他病理条件下，这种行为可能会改变，取而代之的是一种“分离的动态”状态，即这些荷尔蒙的波动不再同步。我们目前对潜在的调节机制缺乏了解，以及它们的干扰是如何导致疾病的，这阻碍了临床医生为越来越多的患有应激相关疾病的患者提供更好的治疗。最近的研究努力集中在了解肾上腺内的调节机制，这些机制控制着应激激素的合成，遵循来自脑下的信号。在这次团契期间，我将建立这些机制的数学模型，并预测疾病期间荷尔蒙动态是如何被破坏的。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充当整合这些荷尔蒙信号并负责它们解离的组织“中枢”。为了探索这一点，我将开发一个数学框架来预测荷尔蒙信号如何控制类固醇合成涉及的因素的表达，包括看似合理的基因调节的生物物理机制。然后，我将进行实验来检验我的模型预测，并展示这些激素是如何调节类固醇生成基因的表达的。最后，我将把我的基因调控模型集成到更大的、多尺度的肾上腺和HPA轴模型中，并使用它们来生成对一些实验、药物治疗以及生理和病理条件的预测。长期目标是了解控制人体内源性应激激素产生的生物学机制，以便我们能够为患有肾上腺功能不全和应激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.