A T Cell-Specific GR promoter Determines Responsiveness to Glucocorticoids in Different Immune Compartments

合成的糖皮质激素，如地塞米松和强的松龙，在治疗人类重大创伤和癌症时，通常被用作有效的抗炎类固醇药物。这些非常高的类固醇剂量的副作用是免疫系统的严重下调，特别是称为T细胞的重要免疫细胞的大量死亡，这可能对患者的康复和潜在的死亡率产生重大影响。这些T细胞对糖皮质激素诱导的细胞死亡特别敏感，并且对这些类固醇受体有非常高的水平，称为糖皮质激素受体(GRs)。我们已经发现了一个独特的GR基因启动子(命名为1A)，它在T细胞中是活跃的。人们对这种基因启动子是如何调控的知之甚少。该启动子可能是一个有用的治疗靶点，以阻止T细胞死亡(由类固醇引起)，在损伤，感染和癌症的恢复过程中。分离抗炎和副作用，如T细胞高度死亡或阻断T细胞的这些作用，将对患者的免疫状态和恢复产生重大影响，并减少衰弱副作用的发生率。这种T细胞特异性GR基因启动子的治疗性下调可能导致类固醇诱导的T细胞死亡的靶向阻断，并有助于维持强大的免疫系统。这一应用程序汇集了一支独特的调查团队(CI)，他们在这一领域有很强的合作历史，最近在非常高级别的国际期刊上发表了文章。Cis结合了内分泌学、分子生物学和细胞免疫学的多学科方法，以确定类固醇作用的潜在机制及其对免疫功能的影响。科尔博士(CIA)和戈弗雷博士(CIB)在这一领域都有出色的记录。

Synthetic glucocorticoids, such as dexamethasone and prednisolone, are commonly used as potent anti-inflammatory steroid drug during the treatment of major human trauma and cancer. A side-effect of these very high steroid doses is a major down-regulation of the immune system, particularly massive death of important immune cells called T-cells, which can have a major impact on patient recovery and potential mortality. These T cells are particularly sensitive to glucocorticoid-induced cell death and have very high levels of receptors for these steroids called glucocorticoid receptors (GRs). We have discovered a unique GR gene promoter (designated 1A) that is active in T cells. Very little is known about how this gene promoter is regulated. This promoter may be a useful therapeutic target to block T cell death (caused by steroids) during recovery from injury, infection and cancer. Separation of anti-inflammatory and side-effects such as high T-cell death or blockade of these effects on T cells would have a major impact on patient immune status and recovery, and reduce the incidence of debilitating side-effects. Therapeutic down-regulation of this T cell-specific GR gene promoter could lead to targeted blockade of steroid-induced T cell death and help maintain a strong immune system. This application brings together a unique team of investigators (CIs) that have a strong history of collaboration in this area with recent publications in very high ranking international journals. The CIs bring a multi-disciplined approach combining endocrinology, molecular biology and cellular immunology to determine the underlying mechanisms of steroid actions and their effects on immune function. Both Dr Cole (CIA) and Dr Godfrey (CIB) have excellent track records in this area.