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

描述（由申请人提供）：GCN2是一种丝氨酸/苏氨酸激酶，在各种细胞应激反应中改变翻译。最近，我们发表的数据表明，GCN2在控制细胞因子产生的脾树突状细胞和巨噬细胞中被激活，以响应凋亡细胞的攻击，从而提示依赖GCN2诱导耐受性的新机制。在本研究中，我们将研究GCN2如何影响凋亡细胞对吞噬细胞的反应，使用GCN2功能完全缺陷或细胞特异性缺陷的小鼠，测试GCN2及其下游效应物C/EBP同源蛋白10 （CHOP）在凋亡细胞诱导的细胞因子产生、吞噬细胞成熟、抗原向T细胞递呈以及抑制适应性T细胞反应和诱导长期耐受的能力中的作用。此外，我们将在小鼠模型中研究GCN2破坏对狼疮发展的影响，并将在狼疮动物模型中测试GCN2激活药物halofuginone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通路操纵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。！

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. !