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

T 细胞特异性 GR 启动子决定不同免疫区室对糖皮质激素的反应

• 批准号: nhmrc : 350302
• 负责人: A/Pr Timothy Cole
• 金额: $ 27.84万
• 依托单位: Monash University
• 依托单位国家: 澳大利亚
• 项目类别: NHMRC Project Grants
• 财政年份: 2005
• 资助国家: 澳大利亚
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://researchdata.edu.au/t-cell-specific-immune-compartments/101221
• 关键词: Cell; Specific; GR; promoter; Determines

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.

合成糖皮质激素，如地塞米松和泼尼松龙，通常用作治疗重大人类创伤和癌症期间的强效抗炎类固醇药物。这些非常高的类固醇剂量的副作用是免疫系统的主要下调，特别是称为T细胞的重要免疫细胞的大量死亡，这可能对患者的恢复和潜在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，并且具有非常高水平的这些类固醇受体，称为糖皮质激素受体（GR）。我们发现了一个独特的GR基因启动子（命名为1A），它在T细胞中有活性。关于这个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，可以在损伤、感染和癌症恢复期间阻断T细胞死亡（由类固醇引起）。将抗炎和副作用（如高T细胞死亡）分开或阻断这些对T细胞的作用将对患者的免疫状态和恢复产生重大影响，并降低使人衰弱的副作用的发生率。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。该应用程序汇集了一个独特的研究人员（CI）团队，他们在该领域有着悠久的合作历史，最近在非常高的国际期刊上发表了文章。CI带来了结合内分泌学，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（中情局）和戈弗雷博士（中情局）在这方面都有出色的记录。