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，从动态的角度更好地理解我们的身体，其中几个生理过程一直在积极变化和适应。事实上，许多健康障碍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，除了分子生物学和生物化学的强大实验技术外，还需要从数学、物理学和计算机科学中借用新的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。这个自我平衡系统通过肾上腺快速合成的应激激素的受控、动态分泌来控制我们身体对压力的反应能力。这发生在脑下垂体分泌的另一种激素刺激之后。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地波动。然而，这种行为在压力和其他病理条件下可能会改变，并被“解离的动态”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的患有应激相关疾病的患者提供更好的治疗。最近的研究工作集中在了解肾上腺内的调节机制，该机制控制垂体信号后应激激素的合成。在此期间，我将开发这些机制的数学模型，并预测疾病期间激素动力学如何被破坏。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的“枢纽”，整合这些激素信号，并负责其dissociation.To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参与类固醇生成的因素的表达，包括合理的生物物理机制的基因调控。然后，我将进行实验来测试我的模型预测，并显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肾上腺和HPA轴的更大的多尺度模型中，并使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.