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，可有效治疗类风湿性关节炎、哮喘、炎症性肠病、多发性硬化症和癌症等疾病。不幸的是，它们的使用受到副作用的限制，这可能是令人痛苦和有害的，服用糖皮质激素的患者报告体重增加，糖尿病，骨变薄，失眠和脂肪分布改变等问题。减少糖皮质激素的副作用，同时保持其抗炎作用，是改善这些容易获得，廉价和易于管理的药物使用的关键。我的主机实验室刚刚发现，糖皮质激素药物的作用是由人体内在的生物钟深刻调节。我们的生物钟由外部信号（如光线和食物）编程，在面对不断变化的外部光线，温度和食物供应时，对于维持身体的内部环境至关重要。我们实验室的工作表明，糖皮质激素受体与基因组中的位点结合，这些位点与核心时钟蛋白、隐花色素（Cry）和REV-ERB的结合位点密切相关。这表明了一种新的机制，涉及启动或阻止糖皮质激素受体进入其靶位点来控制糖皮质激素受体的作用。这样的机制打开了一个治疗的机会，从而糖皮质激素的不良反应可以有针对性的，而不减少其有益的影响。在我的奖学金，我计划调查是否哭确实可以利用减少糖皮质激素的副作用。我还计划研究另一种蛋白质Metadherin的贡献。Metadherin（MTDH）刚刚被揭示为糖皮质激素受体与DNA结合的调节剂，有趣的是，MTDH在肝脏中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。现在我将用这些小鼠来研究昼夜节律的维度，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。我建议使用缺乏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给药的反应。我计划确定隐花色素和Metadherin是否一起工作，并利用这些信息来测试治疗策略，以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.