Analysis of the developmental effects of foetal-maternal thyroid hormone metabolism and signalling using mathematical modelling

已知碘缺乏和甲状腺功能减退症的其他原因会导致人类神经功能缺损，因此通过代谢保持甲状腺激素的稳态对大脑发育至关重要。这项工作的目标是了解甲状腺激素代谢途径的调节，在联合胎儿-母体单位及其对发展的影响。我们将通过扩展我们最近开发的大脑中甲状腺激素稳态的数学模型来做到这一点，该模型是在最近的医学数学研究小组（MMSG）中创建的。MMSG参与者创建了一个新的子模型，包括甲状腺激素代谢和对大脑的影响。在该模型中，血液即外部T4进入神经胶质细胞，并在脱碘酶D2催化的反应中转化为T3。这是由T4-D2复合物的泛素化调节的，其抑制并标记复合物的降解。反过来，T3下调D2的产生。为了模拟这种下调，我们明确包括T3与DNA上的甲状腺激素受体（R）结合以形成结合DNA（DNAB）。与此同时，游离DNA（DNAF）的DNA总量（DNAT）的部分产生mRNA（m），这反过来又产生D2。在附近的神经元中，第二个脱碘酶D3催化T4产生rT 3，T3产生T2。该模型被制定为一个系统的常微分方程（ODE）和作为一个Petri网（PN）-PN是一个基于图形的模型，它在识别生物反应网络中的临界扰动方面很有用，而ODE可以给出定量信息，例如T4的阈值效应浓度等。模拟和数值解表明，在很宽的血液T4浓度范围内，该模型可以维持T3-甲状腺受体复合物水平的体内平衡，然而，存在一个浓度，低于该浓度则不能维持。将该子模型扩展为更生理性的模型，包括T3和T4的全身控制，包括下丘脑-垂体-甲状腺轴的控制和甲状腺激素的肝脏代谢，被确定为进一步研究的活动。这个博士生项目的目标是建立一个适当的模型，结合这三个元素。我们建议利用这个学生项目来推进这项初步工作，开发一个完全定量和验证的全身母亲/胎儿模型，用于甲状腺激素控制。该项目将被细分为以下相互关联的任务：* 扩展MMSG研究组开发的数学模型，以生成大脑中甲状腺激素稳态的完全参数化/验证的子模型。* 使用数学模型来确定循环激素扰动对大脑稳态的潜在长期影响。使用控制分析技术梳理出（快速）脱碘酶调节和（相对缓慢）蛋白质合成过程之间的相互作用，以协调甲状腺激素反应。* 然后，学生将开发一个基于生理学的全身药代动力学（PK）模型，该模型具有身体不同区域的隔间，包括肝脏，血液，甲状腺，大脑和其他组织的隔间。这个模型将连接到我们以前的ODE机制大脑模型。* 学生将开发一个扩展的链接母亲/胎儿PB-PK模型，可用于评估母体甲状腺水平变化对胎儿激素水平的影响。

Iodine deficiency and other causes of hypothyroidism are known to cause neurological deficits in humans and therefore homeostasis of thyroid hormones via metabolism is essential for brain development. The goal of this work is to understand the regulation of thyroid hormone metabolic pathways in the combined foetal-maternal unit and their impact on development. We will do this by extending our recently developed mathematical model of thyroid hormone homeostasis in the brain, created at a recent Maths in Medicine study group (MMSG). The MMSG participants created a novel sub model that consisted of thyroid hormone metabolism and effects in the brain. In this model blood i.e. external T4 enters the glial cell and is turned into T3 in a reaction that is catalysed by a deiodinase D2. This is regulated by the ubiquitination of the T4-D2 complex, which both inhibits and marks the complex for degradation. In turn, T3 downregulates the production of D2. To model this downregulation, we explicitly included the binding of T3 to thyroid hormone receptors (R) on the DNA to form bound DNA (DNAB). Meanwhile the fraction of the total amount of DNA (DNAT) that is free (DNAF) produces mRNA (m), which in turn gives D2. In neurones close by, a second deiodinase D3 catalyses the production of rT3 from T4 and T2 from T3. The model was formulated as a system of ordinary differential equations (ODEs) and as a Petri Net (PN) - the PN is a graphical based model which is useful in identifying critical perturbations within biological reaction networks and the ODEs can give quantitative information e.g. threshold effect concentrations of T4 etc. Simulation and numerical solutions showed that over a wide range of blood T4 concentrations this model could maintain homeostasis of T3-Thyroid Receptor complex levels, however there was a concentration below which this was not maintained. The extension of this sub-model into a more physiological model including the systemic control of T3 and T4 that includes the control of the hypothalamic-pituitary-thyroid axis and liver metabolism of thyroid hormones was identified as an activity for further study. The objective of this PhD studentship is to build an appropriate model that incorporates these three elements.We propose to utilise this studentship to take forward this initial work to develop a fully quantitative and validated whole body mother/foetus model for thyroid hormone control. The project will be subdivided into the following interconnected tasks:* Extend the mathematical models developed at the MMSG study group to generate a fully parameterised/validated submodel of thyroid hormone homeostasis in the brain. * Use the mathematical models to identify potential long term effects on brain homeostasis from circulating hormone perturbations.* Use techniques from control analysis to tease out the interplay between the (rapid) deiodinase regulated and (relatively slow) protein synthesis processes in coordination of the thyroid hormone response. * The student will then develop a whole body physiologically based pharmacokinetic (PK) model with compartments for different areas of the body, including compartments for the liver, blood, thyroid, brain and other tissues. This model will link into our previous ODE mechanistic brain model. * The student will develop an extended linked mother / foetus PB-PK model which can be used to assess the effects of changes in maternal thyroid levels on the hormone levels in the foetus.