Glucocorticoid Receptor Function in Thymocytes

描述（由申请人提供）：我们实验室的长期目标是 确定糖皮质激素（GC）在 免疫系统的发育和免疫系统应答的调节。 GC是最有效的治疗药物之一 自身免疫性和炎症性疾病，以及内源性GC缺乏 生产显着增加自身免疫性，感染性， 炎症性疾病。尽管这些重要后果的过度或 GC对免疫系统功能的作用不足， GC发挥其作用的机制尚未解决。在这 我们将确定关键的靶细胞群， 内源性GC在免疫系统发育过程中起作用， 内源性和外源性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（GR）的作用 和成熟T细胞是形成T细胞库的重要组成部分， 限制免疫系统激活的幅度或持续时间。为了验证这一 假设，我们已经产生了能够条件性失活的小鼠， 发育中的胸腺细胞和T细胞中的GR（T-GR KO小鼠）。在本提案中，我们 将分析T-GR KO小鼠中阳性和阴性选择的效率 在体内，并进一步评估GR在T细胞中的功能， 自身免疫性疾病模型的演变和治疗，实验性自身免疫性 脑脊髓炎（EAE）。基于所获得的知识，新颖且改进 对人类疾病的干预，将治疗性和有害性分开 将阐明GC作用的后果。

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.