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

糖皮质激素介导的基因调控中的盐皮质激素受体：MR/GR 相互作用和染色质可及性作为机制

• 批准号: BB/L007622/1
• 负责人: Stafford Lightman
• 金额: $ 87.28万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FL007622%2F1
• 关键词: mineralocorticoid; receptor; glucocorticoid; mediated; gene

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

皮质醇是一种在血液中循环的自然荷尔蒙，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枢的一个主要因素。皮质醇正常调节的中断与精神疾病有关，包括严重的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，本身也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增加对这些日益常见的疾病易感性的主要因素。脑细胞对皮质醇的反应是通过一种名为糖皮质激素受体(GR)的蛋白质来实现的，这种蛋白质已经得到了很好的研究，并通过盐皮质激素受体(MR)蛋白来做出反应，而对这种蛋白质的了解要少得多。人们认为，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非常重要，而失衡会导致精神症状。然而，我们对MR和GR如何通过正确阅读和解释DNA中的遗传蓝图来产生“正常”的大脑功能知之甚少。当受体水平失衡时，当皮质醇模式改变时，或者当使用类似皮质醇的合成激素治疗患者时，我们更不知道这个过程是如何出错的。由于MR和GR经常出现在同一个脑细胞中，我们预测，正常的大脑环境是通过皮质醇兴奋时两者的协同作用而产生的。我们想要研究这种MR/GR合作在细胞中的影响程度，以及它是如何在MR/GR与存储指令库(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会如何随着合成荷尔蒙的异常模式和类型；或MR/GR水平的异常而改变。因此，这项工作暗示了这种变化是如何导致精神疾病的。MR和GR控制控制细胞功能的DNA指令的复制，就像复印机从手册上复制页面一样。我们将首先发现DNA的哪些部分的复制同时由MR和GR控制，以及通过观察DNA上它们一起被发现的地方，合作活动是多么广泛。接下来，我们将查看协作功能如何发生以及这对复制过程产生的影响的精选示例。MR/GR的物理相互作用是一种可能产生独特结果的可能性。我们将确定是否是这种情况，并定义交互中的MRS和GR的数量，评估这个数字是否会在不同的情况下发生变化。MR/GR还可以独立地与站点交互，这意味着通过每个站点的行动平衡产生最终结果。例如，其中一种蛋白质可能小心地控制另一种蛋白质与DNA相互作用的能力，或者这些活动可能是互补的，也可能是相反的。这些可能性也将受到考验。在活细胞内解决这些问题并不容易，所以我们来到美国学习研究这些问题的新方法，并将在我们确定MR/GR协同工作的正常方式时将这些方法返回英国。最后，皮质醇分泌模式可能会产生MR和GR协同工作的特定时间，因此我们将确定MR和GR在这一模式中的哪个部位同时活跃。这将提供更多关于疾病相关皮质醇模式和浓度，或合成激素或MR/GR水平失衡的存在，如何误导MR/GR协同机制，导致对可能开始疾病过程的细胞指令的改变解释的进一步洞察

项目成果

A Time for Metabolism and Hormones

• DOI: 10.1007/978-3-319-27069-2
• 发表时间: 2016
• 作者: P. Sassone-Corsi;Y. Christen

The emerging importance of ultradian glucocorticoid rhythms within metabolic pathology.

• DOI: 10.1016/j.ando.2018.03.003
• 发表时间: 2018-06
• 期刊: Annales d'endocrinologie
• 作者: Flynn BP;Conway-Campbell BL;Lightman SL
• 通讯作者: Lightman SL

Genome-Wide Identification of Basic Helix-Loop-Helix and NF-1 Motifs Underlying GR Binding Sites in Male Rat Hippocampus.

• DOI: 10.1210/en.2016-1929
• 发表时间: 2017-05-01
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Pooley JR;Flynn BP;Grøntved L;Baek S;Guertin MJ;Kershaw YM;Birnie MT;Pellatt A;Rivers CA;Schiltz RL;Hager GL;Lightman SL;Conway-Campbell BL
• 通讯作者: Conway-Campbell BL