Glucocorticoid receptor acetylation and corticosteroid resistance in chronic obstructive pulmonary disease

慢性阻塞性肺疾病（COPD）或吸烟者？肺是一个日益严重的问题，已经是英国最常见的死亡和残疾原因之一。它与肺部炎症有关，随着疾病的进展，肺部炎症会变得更糟。哮喘还涉及肺部炎症，但这通常很容易用类固醇吸入器控制，这是非常有效的治疗方法。相比之下，COPD患者的炎症对类固醇治疗没有反应，我们已经证明COPD患者的细胞也没有反应，这表明这个问题可能是由于分子缺陷。类固醇通过与一种称为糖皮质激素受体（GR）的特异性识别蛋白结合而起作用，这种蛋白进入细胞核并关闭编码炎症产物的基因，同时打开其他导致副作用的基因。我们发现，当GR与类固醇相互作用时，它会被乙酰化改变，但如果它要关闭炎症基因并控制炎症，则必须被称为脱乙酰酶的酶改变回来。我们还发现，这些脱乙酰酶在COPD患者的细胞中明显缺陷，因此GR不太能够转化为关闭炎症基因所需的形式，从而解释了这些患者对类固醇缺乏反应。该项目的目的是研究GR的乙酰化和去乙酰化以及如何在COPD细胞中改变。我们希望这将提供一种逆转这种异常的方法，并最终开发出使类固醇在治疗COPD中更有效的治疗方法。由于目前没有抗炎治疗方法用于治疗COPD，并且戒烟对炎症的影响很小或没有影响，因此迫切需要了解类固醇抵抗的机制并找到可能逆转这种情况的治疗方法。同样的机制在其他严重的炎症性疾病中也可能很重要，例如关节和肠道的炎症性疾病，因此这项研究对健康的影响可能是巨大的。我们在帝国理工学院有一个优秀的媒体关系部门，通常会在发表时宣传任何具有公共利益的研究。如果强调这种疾病中巨大的未满足的需求，那么在理解潜在机制方面的任何进展都可以以非常有利的方式呈现。

Chronic obstructive pulmonary disease (COPD) or smokers? lung is a growing problem and already one of the commonest causes of death and disability in the UK. It is associated with inflammation in the lung, which gets worse as the disease progresses. Asthma also involves inflammation in the lung but this is usually easy to control with steroid inhalers, which are very effective treatment. By contrast, the inflammation in COPD does not respond to steroid therapy and we have shown that cells from COPD patients also fail to respond, indicating that this problem is likely to be due to a molecular defect. Steroids work by binding to a specific recognition protein called a glucocorticoid receptor (GR) which goes into the nucleus of the cell and switches off genes that code for inflammatory products whereas switching on other genes that lead to side effects. We have found that GR becomes changed by acetylation when it interacts with a steroid, but has to be changed back by enzymes called deacetylases if it is to switch off inflammatory genes and control inflammation. We have also found that these deacetylases are markedly defective in cells from COPD patients so GR is less able to be converted to a form which is needed to switch off inflammatory genes, thus accounting for the lack of response to steroids in these patients. The aim of this project is to study acetylation and deacetylation of GR and how this is altered in COPD cells. We hope that this will provide a means to reverse this abnormality and eventually to the development of treatments that will make steroids more effective in the treatment of COPD. As no anti-inflammatory treatments currently exist for the treatment of COPD and stopping smoking does appear to little or no effect on the inflammation, there is an urgent need to understand the mechanisms of steroid resistance and to find treatments that may reverse this situation. The same mechanisms may also be important in other severe inflammatory diseases, such as inflammatory diseases of joints and the gut, so that the health implications of this research are potentially enormous. We have an excellent Media Relations Department at Imperial College and commonly publicise any research that has public interest when it is published. Any advance in understanding the underlying mechanisms could be presented in a very favourable light if the enormous unmet needs in this disease are emphasised.