Glucocorticoid Receptor function in Thymocytes

胸腺细胞中的糖皮质激素受体功能

• 批准号: 6722756
• 负责人: Louis J Muglia
• 金额: $ 30.6万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6722756
• 关键词: T lymphocyte; autoimmunity; corticosteroid receptors; cytokine; developmental immunology; disease /disorder model; experimental allergic encephalomyelitis; flow cytometry; genetically modified animals; glucocorticoids; hormone regulation /control mechanism; in situ hybridization; laboratory mouse; multiple sclerosis; protein biosynthesis; thymus

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.

描述（由申请人提供）：我们实验室的长期目标是明确糖皮质激素（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。 GC 是可用于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 产生的缺乏会显着增加自身免疫性、感染性和炎症性疾病的严重程度。尽管 GC 作用过度或不足对免疫系统功能产生了这些重要后果，但 GC 发挥其作用的重要位点和机制尚未得到解决。在本提案中，我们将确定内源性GC在免疫系统发育过程中发挥作用的关键靶细胞群，以及内源性和药物施用的GC影响自身免疫/炎症性疾病的进化和治疗的机制。我们假设 GC 对发育中的胸腺细胞和成熟 T 细胞内糖皮质激素受体 (GR) 的作用是塑造 T 细胞库和限制免疫系统激活的程度或持续时间的重要组成部分。为了验证这一假设，我们培育了能够在胸腺细胞和 T 细胞发育过程中条件性使 GR 失活的小鼠（T-GR KO 小鼠）。在本提案中，我们将分析 T-GR KO 小鼠体内正向和负向选择的效率，[以及细胞因子产生的调节]，并进一步评估 T 细胞中 GR 在进化和治疗过程中的功能。模型自身免疫性疾病，实验性自身免疫性脑脊髓炎（EAE）。根据所获得的知识，将阐明针对人类疾病的新颖且改进的干预措施，将GC作用的治疗后果和有害后果分开。