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

描述（由申请人提供）：一般对照非阻遏2（GCN 2）是一种丝氨酸/苏氨酸激酶，其响应于各种细胞应激而改变翻译。最近，我们发表的数据表明，GCN 2在控制细胞因子产生的脾树突状细胞和巨噬细胞中响应凋亡细胞挑战而被激活，从而表明依赖于GCN 2的耐受诱导的新机制。在该提案中，我们将使用GCN 2功能完全或细胞特异性缺陷的小鼠来检查GCN 2如何影响吞噬细胞对凋亡细胞的应答，测试GCN 2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、抗原呈递给T细胞、以及抑制适应性T细胞应答和在皮肤同种异体移植模型中诱导长期耐受的能力。此外，我们将研究GCN 2破坏对小鼠模型中狼疮发展的影响，并将测试GCN 2激活药物常山酮在疾病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GCN 2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理论基础。!

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. !