Novel anti-inflammatory mechanisms of the Glucocorticoid Receptor

糖皮质激素受体的新抗炎机制

• 批准号: 24920688
• 负责人: Professor Dr. Jan Tuckermann
• 金额: --
• 依托单位: Institut für Molekulare Endokrinologie der Tiere
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/24920688?language=en
• 关键词: Novel; anti; inflammatory; mechanisms; Glucocorticoid

Glucocorticoid hormones (GC) are potent anti-inflammatory agents, which are widely used in therapy. However, their usefulness is limited by catabolic side effects that often occur during GC treatment. They strongly compromise the quality of life of the patients and cause additional treatment costs in the order of hundreds of million ¿. It is therefore of great importance to understand the molecular mechanisms by which GC exert their anti-inflammatory as well as their catabolic action in order to develop new and more specific drugs and treatments. The currently accepted view in the field attributes the anti-inflammatory action of GC to mechanisms which do not depend on DNA binding by the glucocorticoid receptor (GR), whereas side effect are believed to be mediated by dimerization-dependent DNA-binding. However, in unpublished studies we showed that in murine models for contact allergy and sepsis, DNA binding of the GR is required for the immune suppressive activity of GC. Mice lacking the dimerization-induced DNA binding function of the GR (GRdim mice) do not react to GC in these disease paradigms. By expression profiling and RT-PCR analysis of macrophages derived from GRdim mice, we identified genes that are regulated by GC in wild type, but not in GRdim cells. These genes are putative candidates for the mechanisms involved in mediating GCinduced anti-inflammatory action. We intend to analyze the function of these GC modulated genes by cell culture assays, in tissues of disease models and in in vivo models of these diseases. We further plan to study the regulation of these genes by the dimerizing GR in the context of their promoters, and of interacting factors that are required for this regulation. We hope to thus identify novel pathways involved in GC function. This could lead to new models for improved therapies and to the identification of novel anti-inflammatory drug targets.

糖皮质激素（GC）是一种有效的抗炎药物，广泛应用于治疗。然而，它们的有用性受到GC治疗期间经常发生的分解代谢副作用的限制。它们严重损害了患者的生活质量，并导致数亿美元的额外治疗费用。因此，了解GC发挥其抗炎作用以及其分解代谢作用的分子机制以开发新的和更具体的药物和治疗是非常重要的。本领域目前接受的观点将GC的抗炎作用归因于不依赖于糖皮质激素受体（GR）的DNA结合的机制，而副作用被认为是由二聚化依赖性DNA结合介导的。然而，在未发表的研究中，我们发现在接触性变态反应和脓毒症的小鼠模型中，GR的DNA结合是GC的免疫抑制活性所必需的。缺乏GR二聚化诱导的DNA结合功能的小鼠（GRdim小鼠）在这些疾病范例中不对GC反应。通过表达谱分析和RT-PCR分析来自GRdim小鼠的巨噬细胞，我们确定了在野生型中受GC调控的基因，但在GRdim细胞中不受GC调控。这些基因是参与介导GC诱导的抗炎作用的机制的假定候选者。我们打算通过细胞培养试验，在疾病模型的组织和这些疾病的体内模型中分析这些GC调节基因的功能。我们进一步计划研究这些基因的调节，由二聚GR在其启动子的背景下，和相互作用的因素，这是必要的调节。因此，我们希望确定参与GC功能的新途径。这可能会导致新的模型，以改善治疗和识别新的抗炎药物的目标。