Glucocorticoid Receptor function in Thymocytes

描述(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反应调节中的作用和作用机制。GCS是治疗自身免疫性和炎症性疾病的最有效的药物之一，内源性GC产生不足会显著增加自身免疫性、感染性和炎症性疾病的严重程度。尽管GC过度或不充分对免疫系统功能产生了这些重要后果，但GC发挥作用的基本部位和机制仍未解决。在这个建议中，我们将确定内源性GCs在免疫系统发育过程中作用的关键靶细胞群，以及内源性GCs和药物给药对自身免疫/炎症性疾病的进化和治疗的影响机制。我们假设GC对发育中的胸腺细胞和成熟的T细胞中的糖皮质激素受体(GR)的作用是形成T细胞谱系和限制免疫系统激活的幅度或持续时间的重要组成部分。为了验证这一假设，我们培育了能够在发育中的胸腺细胞和T细胞中有条件地使GR失活的小鼠(T-GR KO小鼠)。在这项研究中，我们将分析T-GR KO小鼠体内正负选择[和细胞因子产生的调节]的效率，并进一步评估T细胞中GR在实验性自身免疫性脑脊髓炎(EAE)模型的进化和治疗过程中的功能。在已有知识的基础上，将阐明针对人类疾病的新的和改进的干预措施，即GC行动的治疗和有害后果的分离。

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.