The mineralocorticoid receptor in glucocorticoid-mediated gene regulation: MR/GR interactions and chromatin accessibility as mechanisms

皮质醇是一种通过血液循环的天然激素，对大脑起作用，调节脑细胞相互传递信号的方式，以及学习和记忆等过程。它也是调节情绪、焦虑和健康的大脑中心的一个主要因素。皮质醇正常调节的中断与精神疾病有关，包括重度抑郁症和创伤后应激障碍。压力在皮质醇释放的激活中起着重要作用，并且它本身与精神疾病的发病直接相关。现在有大量证据表明，皮质醇分泌模式的变化是这些日益常见的疾病的易感性增加的主要因素。脑细胞对皮质醇的反应是通过糖皮质激素受体（GR）和矿物皮质激素受体（MR）两种蛋白质进行的，这两种蛋白质已经得到了很好的研究。据信，MR和GR的平衡活动对正常的大脑功能和对压力情况的反应很重要，而不平衡会导致精神症状。然而，我们对MR和GR如何通过正确读取和解释DNA中的遗传蓝图来共同产生“正常”的大脑功能知之甚少。当受体水平不平衡时，当皮质醇模式改变时，或者当使用类似皮质醇的合成激素治疗病人时，我们对这个过程是如何出错的就更不了解了。由于MR和GR通常存在于相同的脑细胞中，我们预测正常的大脑环境是在皮质醇激活它们时通过两者的协同作用产生的。我们想要研究这种MR/GR合作在细胞中的影响有多深，以及它是如何在MR/GR与细胞存储指令库（DNA）相互作用的水平上产生的。我们在这里的大部分工作将旨在了解什么是“正常”，但实验也将暗示正常情况如何随着异常模式和合成激素的类型而改变；或MR/GR异常。因此，这项工作暗示了这些变化是如何导致精神疾病的。MR和GR调节控制细胞功能的DNA指令的复制，就像复印机从手册中复制页面一样。我们将首先发现DNA的哪些部分的复制同时受到MR和GR的控制，以及通过观察它们在DNA上一起出现的位置，它们的合作活动有多广泛。接下来，我们将选择一些例子，看看协作功能是如何发生的，以及它对复制过程的影响。MR/GR的物理相互作用是可能产生独特结果的一种可能性。我们将确定情况是否如此，并定义相互作用中的mr和gr的数量，评估这个数字在不同情况下是否会变化。MR/GR也可能独立地与站点交互，这意味着通过每个操作的平衡产生最终结果。例如，其中一种蛋白质可能会小心地控制另一种蛋白质与DNA相互作用的能力，或者它们的活动可能互补或相反。这些可能性也将受到考验。在活细胞内部解决这些问题并不容易，因此我们前往美国学习研究这些问题的新方法，并将这些方法带回英国，因为我们定义了MR/GR协同作用的正常工作方式。最后，皮质醇分泌模式可能会产生MR和GR协同作用的特定时间，因此我们将确定MR在此模式中与GR同时活跃的位置。这将为疾病相关的皮质醇模式和浓度，或合成激素或MR/GR水平不平衡的存在提供额外的见解，误导MR/GR协同机制，导致可能开始疾病过程的细胞指令解释改变

Cortisol is a natural hormone that circulates through the blood and acts on the brain to regulate the ways brain cells signal to each other and processes such as learning and memory. It is also a major factor in the regulation of brain centres that regulate mood, anxiety and wellbeing. Disruptions in the normal regulation of cortisol have been linked to psychiatric disease including major depression and post-traumatic stress disorder.Stress plays a major role in the activation of cortisol release and has itself been linked directly with the onset of psychiatric illness. There is now a large body of evidence that changes in the pattern of cortisol secretion is a major factor in increasing vulnerability to these increasingly common disorders.Brain cells respond to cortisol though a protein called the glucocorticoid receptor (GR) which has been well studied, and by the mineralocorticoid receptor (MR) protein about which much less is known. It's believed that the balanced activity of MR and GR is important for normal brain function and responses to stressful situations, and that imbalances lead to psychiatric symptoms. Yet we know very little about how by working together the MR and GR produces 'normal' brain function by correctly reading and interpreting the genetic blue print in DNA. We know even less about how this process goes wrong when the receptor levels are imbalanced, when the cortisol pattern changes, or when synthetic hormones similar to cortisol are used to treat patients.Because MR and GR are often present in the same brain cells we predict the normal brain environment is produced via the cooperative action of both when cortisol turns them on. We would like to study how far reaching this MR/GR cooperation is in a cell, and how it arises at a level of MR/GR interacting with the cells library of stored instructions (DNA). The bulk of our work here will aim to understand what is 'normal', but experiments will also hint at how the normal situation can change with abnormal patterns and types of synthetic hormones; or abnormal levels of MR/GR. This work therefore hints at how such changes can contribute to psychiatric disease.MR and GR regulate the copying of DNA instructions that control the cells function, like a photocopier copies pages from a manual. We'll first discover which parts of the DNA have their copying controlled by both MR and GR, and how widespread cooperative activity is by looking at where on DNA they are found together. We'll next look at selected examples of how cooperative function might occur and the effect this has on the copying process. A physical interaction of MR/GR is one possibility that could produce a unique outcome. We'll determine if this is the case and also define the number of MRs and GRs within the interaction, assessing whether this number can change under different circumstances. MR/GR might also interact with a site independently meaning the balance of actions through each produces the final outcome. One of the proteins may carefully control the ability of the other to interact with the DNA for example, or the activities maybe complementary or opposite to each other. These possibilities will also be tested. These are not easy questions to address inside a living cell so we have travelled to the USA to learn new ways to study these questions and will return these methods to Britain as we define ways in which MR/GR cooperativity normally works.Finally, the pattern of cortisol secretion likely produces specific times at which MR and GR can function cooperatively so we will determine where in this pattern MR is active at the same time as GR. This will provide additional insight into how disease-associated cortisol patterns and concentrations, or the presence of synthetic hormones or imbalanced MR/GR levels, misdirects the MR/GR cooperativity mechanisms leading to altered interpretation of cellular instructions that may begin disease proces