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定义糖皮质激素（GCS）在免疫系统开发和免疫系统反应的调节中的作用和机理。 GC是可用于治疗自身免疫性和炎症性疾病的最有效的药理学剂之一，内源性GC产生的缺陷大大增加了自身免疫，感染性和炎症性疾病的严重程度。尽管对免疫系统功能的过量或GC作用不足产生了这些重要的后果，但GC施加效果的基本位点和机制仍未解决。在此提案中，我们将确定内源性GC在免疫系统发育过程中起作用的关键靶细胞种群，以及内源性和药理学对GC对自身免疫/炎症性疾病的进化和治疗的机制。我们假设在发育中的胸腺细胞和成熟的T细胞内对糖皮质激素受体（GR）的GC作用是塑造T细胞库的重要组成部分，并限制了免疫系统激活的幅度或持续时间。为了检验这一假设，我们已经产生了能够在发育中的胸腺细胞和T细胞（T-GR KO小鼠）中有条件地失活的小鼠。在该提案中，我们将分析体内T-Gr Ko小鼠的正选择和阴性选择的效率，并[和调节细胞因子的产生]，并进一步评估T-Cell在T细胞中GR在模型自身免疫性疾病的进化和治疗过程中的功能，实验性的自身免疫性疾病（EAE）。基于获得的人类疾病的知识，新颖和改善的干预措施，将阐明GC作用的分开治疗和有害后果。