Elucidating clock control of glucocorticoid action

糖皮质激素是一种类固醇激素，是广泛使用的抗炎药物，对类风湿关节炎、哮喘、炎症性肠病、多发性硬化症和癌症等疾病提供有效治疗。不幸的是，它们的使用受到副作用的限制，这些副作用既令人痛苦又有害，服用糖皮质激素的患者报告体重增加、糖尿病、骨质疏松、失眠和脂肪分布改变等问题。尽量减少糖皮质激素的副作用，同时保持其抗炎作用，是改善这些可获得、廉价和易于管理的药物使用的关键。我的宿主实验室刚刚发现糖皮质激素药物的作用受到人体内在生物钟的深刻调控。我们的生物钟是由光线和食物等外部信号控制的，面对外界光线、温度和食物的变化，它在维持身体内部环境方面至关重要。我们实验室的研究表明，糖皮质激素受体与基因组中与核心时钟蛋白、Cryptochrome （Cry）和REV-ERB的结合位点密切相关的位点结合。这提示了一种控制糖皮质激素受体作用的新机制，包括启动或阻止糖皮质激素受体进入其靶位点。这种机制为治疗提供了机会，使糖皮质激素的不良作用可以被靶向，而不会减少其有益作用。在我的研究中，我计划调查是否可以确实利用哭泣来减少糖皮质激素的副作用。我还计划研究另一种蛋白质的作用，Metadherin。Metadherin （MTDH）刚刚被发现是糖皮质激素受体与DNA结合的调节剂，令人着迷的是，肝脏中MTDH的表达受昼夜节律控制。我的宿主实验室已经获得了MTDH敲除小鼠，在早期的工作中，这些小鼠显示出明显的体内糖皮质激素表型。我现在要用这些老鼠来研究昼夜节律。我的假设是生物钟通过隐花色素和Metadherin来调节糖皮质激素的作用。我建议用缺乏Cry或MTDH的小鼠来测试这一点，并测量对急性和慢性糖皮质激素治疗的反应。我计划确定是否隐色素和甲沙丁一起工作，并利用这些信息来测试治疗策略，目的是减少糖皮质激素的副作用。

Glucocorticoids, a type of steroid hormone, are widely-used anti-inflammatory drugs which provide effective treatment for conditions such as rheumatoid arthritis, asthma, inflammatory bowel disease, multiple sclerosis and cancer. Unfortunately, their use is limited by side effects, which can be both distressing and harmful, with patients taking glucocorticoids reporting weight gain, diabetes, bone-thinning, insomnia, and altered fat distribution, amongst other problems. Minimising the side effects of glucocorticoids, whilst preserving their anti-inflammatory action, is key to improving the use of these accessible, cheap, and easy-to-administer drugs.My host laboratory has just discovered that the action of glucocorticoid drugs is profoundly regulated by the body's intrinsic circadian clock. Our body clock, programmed by external signals such as light and food, is critical in maintaining the body's internal environment in the face of changing outside light, temperature and food availability. Work from our laboratory shows that the glucocorticoid receptor binds to sites in the genome which are closely related to binding sites for the core clock proteins, Cryptochrome (Cry), and REV-ERB. This suggests a novel mechanism operating to control glucocorticoid receptor action, involving priming, or preventing access of the glucocorticoid receptor to its target sites. Such a mechanism opens a therapeutic opportunity whereby the adverse effects of glucocorticoids could be targeted, without reducing their beneficial effects.In my Fellowship, I plan to investigate whether Cry can indeed be exploited to reduce glucocorticoid side effects. I also plan to investigate the contribution of another protein, Metadherin. Metadherin (MTDH) has just been revealed as a regulator of glucocorticoid receptor binding to DNA, and fascinatingly, MTDH expression in the liver lies under circadian control. My host lab has obtained MTDH knockout mice, and in early work, these show a marked in-vivo glucocorticoid phenotype. I will now investigate the circadian dimension, using these mice.My hypothesis is that the clock acts through Cryptochrome, and Metadherin, to regulate glucocorticoid action. I propose to test this using mice lacking Cry, or MTDH, and measure responses to acute and chronic glucocorticoid administration. I plan to determine whether or not Cryptochrome and Metadherin work together, and to use this information to test therapeutic strategies with the aim of reducing glucocorticoid side effects.