The role of GCN2-kinase in antigen presenting cell function and tolerance to self

GCN2激酶在抗原呈递细胞功能和自身耐受性中的作用

• 批准号: 8583790
• 负责人: Tracy L McGaha
• 金额: $ 21.15万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-16 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8583790
• 关键词: Amino Acids; Animal Disease Models; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apoptotic; Autoimmune Diseases; Autoimmunity; CCAAT-Enhancer-Binding Proteins; Cell Death; Cell physiology; Cells; Cellular Stress; Characteristics; Data; Defect; Dendritic Cells; Development; Dioxygenases; Disease; Enzymes; Excision; Genes; Halofuginone; Homologous Protein; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunologics; Immunosuppression; Individual; Inflammatory; Lupus; Modeling; Molecular; Mus; Organ; Pathogenesis; Pathology; Pathway interactions; Phagocytes; Pharmaceutical Preparations; Phosphotransferases; Play; Prevention; Production; Publishing; Regulatory Pathway; Research; Role; System; Systemic Lupus Erythematosus; T cell response; T-Lymphocyte; Testing; Time; Translations; Tryptophan; Withdrawal; base; biological adaptation to stress; blood filter; cytokine; indoleamine; macrophage; mouse model; novel; prevent; public health relevance; response; skin allograft; systemic autoimmune disease; therapeutic target

DESCRIPTION (provided by applicant): General control non-repressed 2 (GCN2) is a ser/thr kinase that alters translation in response to various cellular stresses. Recently we published data suggesting that GCN2 is activated in response to apoptotic cell challenge in splenic dendritic cells and macrophages controlling cytokine production, thus suggesting a novel mechanism of tolerance induction dependent on GCN2. In this proposal we will examine how GCN2 influences phagocyte responses to apoptotic cells using mice with a complete or cell specific defects in GCN2 function testing the role of GCN2 and its downstream effector C/EBP homologous protein 10 (CHOP) in apoptotic cell induced cytokine production, phagocyte maturation, antigen presentation to T cells, and ability to suppress adaptive T cell responses and induce long-term tolerance in a skin allograft model. Moreover we will examine the impact of GCN2 disruption on development of lupus in mouse models and will test the ability of the GCN2 activating drug, halofuginone, to inhibit autoimmunity development and disease pathology in animal models of the disease. Thus, the project will provide key mechanistic rationale to explore GCN2 pathway manipulation as a therapeutic target in lupus and other autoimmune diseases. !

描述(申请人提供)：一般控制非抑制2(GCN2)是一种丝氨酸/苏氨酸激酶，改变翻译以响应各种细胞压力。最近我们发表的数据表明，在控制细胞因子产生的脾树突状细胞和巨噬细胞中，GCN2被激活以响应凋亡细胞的挑战，从而提出了一种依赖GCN2诱导耐受的新机制。在这项建议中，我们将使用GCN2功能完全或细胞特异性缺陷的小鼠来研究GCN2如何影响吞噬细胞对凋亡细胞的反应，测试GCN2及其下游效应因子C/EBP同源蛋白10(CHOP)在同种异体皮肤移植模型中凋亡细胞诱导的细胞因子产生、吞噬细胞成熟、抗原呈递T细胞以及抑制适应性T细胞反应和诱导长期耐受中的作用。此外，我们还将研究GCN2干扰对狼疮小鼠模型发展的影响，并将测试GCN2激活剂常氟酮在狼疮动物模型中抑制自身免疫发展和疾病病理的能力。因此，该项目将为探索GCN2通路操作作为狼疮和其他自身免疫性疾病的治疗靶点提供关键的机制基础。好了！