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）在免疫系统发育和免疫系统应答调节中的作用和作用机制。GC是可用于治疗自身免疫性和炎性疾病的最有效的药理学试剂之一，并且内源性GC产生的缺乏显著增加了自身免疫性、感染性和炎性疾病的严重性。尽管GC对免疫系统功能的作用过量或不足会产生这些重要后果，但GC发挥其作用的重要部位和机制尚未得到解决。在这个提议中，我们将确定关键的靶细胞群体，内源性GC在免疫系统发育过程中发挥作用，以及内源性和非内源性GC对自身免疫性/炎症性疾病的演变和治疗产生影响的机制。我们假设GC对发育中的胸腺细胞和成熟T细胞内的糖皮质激素受体（GR）的作用是塑造T细胞库和限制免疫系统激活的幅度或持续时间的重要组成部分。为了验证这一假设，我们已经产生了能够在发育中的胸腺细胞和T细胞中条件性失活GR的小鼠（T-GR KO小鼠）。在这项提案中，我们将分析T-GR KO小鼠体内阳性和阴性选择的效率，[和细胞因子产生的调节]，并进一步评估GR在模型自身免疫性疾病，实验性自身免疫性脑脊髓炎（EAE）的演变和治疗过程中T细胞中的功能。基于所获得的知识，将阐明用于人类疾病的新的和改进的干预措施，即GC作用的单独治疗和有害后果。

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, [and regulation of cytokine production] 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.