Glucocorticoid Receptor Function in Thymocytes

描述(申请人提供)：我们实验室的长期目标是 明确糖皮质激素(GC)的作用和作用机制 免疫系统的发展和免疫系统反应的调节。 GCS是治疗这种疾病的最有效的药物之一。 自身免疫性和炎症性疾病，内源性GC缺乏 生产极大地增加了自身免疫、传染性和 炎症性疾病。尽管过度或过度的重要后果 GC对免疫系统功能、必需部位和 GC发挥作用的机制尚未解决。在这 提案，我们将确定关键的目标细胞群体， 内源性GC在免疫系统发育过程中发挥作用，其机制是通过 哪些内源性和药物给药的GC对 自身免疫性/炎症性疾病的演变和治疗。我们假设 GC对发育中胸腺细胞糖皮质激素受体的作用 和成熟的T细胞是形成T细胞谱系和 限制免疫系统激活的幅度或持续时间。为了测试这一点 假设，我们已经产生了能够有条件地灭活 GR在胸腺细胞和T细胞(T-GR KO小鼠)发育中的作用。在这项提案中，我们 将分析T-GR KO小鼠正选择和负选择的效率 ，并进一步评价GR在T细胞中的功能。 实验性自身免疫性疾病模型的演变与治疗 脑脊髓炎(EAE)。在已有知识的基础上，创新和改进 对人类疾病的干预，将治疗和有害分开 GC作用的后果将被阐明。

DESCRIPTION (provided by applicant): The long-term goal of our laboratory is to define the role and mechanism of action of glucocorticoids (GCs) in the development of the immune system and the modulation of immune system responses. GCs are among the most potent pharmacologic agents available for the treatment of autoimmune and inflammatory disorders, and deficiency of endogenous GC production dramatically increases the severity of autoimmune, infectious, and inflammatory diseases. Despite these important consequences of excess or inadequate GC action for immune system function, the essential sites and mechanisms by which GCs exert their effects have gone unresolved. In this proposal, we will determine the critical target cell populations upon which endogenous GCs act during immune system development, and the mechanisms by which endogenous and pharmacologically administered GCs impact upon the evolution and treatment of autoimmune/inflammatory disease. We hypothesize that GC actions on the glucocorticoid receptor (GR) within the developing thymocyte and mature T-cell are important components in shaping the T-cell repertoire and limiting the magnitude or duration of immune system activation. To test this hypothesis, we have generated mice capable of conditional inactivation of the GR in developing thymocytes and T-cells (T-GR KO mice). In this proposal, we will analyze the efficiency of positive and negative selection in T-GR KO mice in vivo, and further evaluate the function of the GR in T-cells during the evolution and treatment of a model autoimmune disease, experimental autoimmune encephalomyelitis (EAE). Based upon the knowledge gained, novel and improved interventions for human disease, that separate therapeutic and harmful consequences of GC action, will be elucidated.