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

皮质醇是一种天然激素，通过血液循环作用于大脑，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主要因素。皮质醇的正常调节受到干扰与精神疾病有关，包括严重抑郁症和创伤后应激障碍。压力在激活皮质醇释放方面起着重要作用，其本身与精神疾病的发作直接相关。现在有大量的证据表明，皮质醇分泌模式的改变是增加对这些日益常见的疾病的易感性的一个主要因素，脑细胞通过一种被称为糖皮质激素受体（GR）的蛋白质和盐皮质激素受体（MR）蛋白质对皮质醇做出反应，糖皮质激素受体（GR）已经得到了很好的研究，而盐皮质激素受体（MR）蛋白质则知之甚少。据信，MR和GR的平衡活动对于正常的大脑功能和对压力情况的反应是重要的，并且不平衡会导致精神症状。然而，我们对MR和GR如何通过正确阅读和解释DNA中的遗传蓝图来共同发挥“正常”大脑功能知之甚少。当受体水平失衡时，当皮质醇模式改变时，或者当使用类似于皮质醇的合成激素来治疗患者时。因为MR和GR通常存在于相同的脑细胞中，我们预测当皮质醇打开它们时，正常的大脑环境是通过两者的协同作用产生的。我们想研究这种MR/GR的影响有多大。GR合作是在细胞中，以及它如何在MR/GR与细胞存储指令（DNA）库相互作用的水平上产生。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合成激素的异常模式和类型而改变;因此，这项工作暗示了这种变化如何导致精神疾病。MR和GR调节控制细胞功能的DNA指令的复制，就像复印机复印手册一样。我们将首先发现DNA的哪些部分的复制受到MR和GR的控制，以及通过观察它们在DNA上的位置发现它们在一起的合作活动有多广泛。接下来，我们将选择一些例子来说明合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。我们将确定是否是这种情况，并定义交互中MR和GR的数量，评估该数量是否可以在不同情况下改变。MR/GR也可能独立地与一个位点相互作用，这意味着通过每个位点的作用平衡产生最终结果。例如，其中一种蛋白质可能会仔细控制另一种蛋白质与DNA相互作用的能力，或者这些活性可能相互互补或相反。这些可能性也将受到考验。这些问题在活细胞内并不容易解决，因此我们前往美国学习研究这些问题的新方法，并将在我们定义MR/GR协同性正常工作的方式时将这些方法返回英国。皮质醇分泌的模式可能产生MR和GR可以协同作用的特定时间，因此我们将确定在这种模式中MR同时活跃的位置，这将提供对疾病相关的皮质醇模式和浓度，或合成激素或不平衡的MR/GR水平的存在如何误导MR/GR协同机制的额外了解，从而导致可能开始疾病过程的细胞指令的改变的解释

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