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: 8662697
• 负责人: Tracy L McGaha
• 金额: $ 18.75万
• 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/8662697
• 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（由申请人提供）：通用对照非抑制 2 (GCN2) 是一种丝氨酸/苏氨酸激酶，可响应各种细胞应激而改变翻译。最近我们发表的数据表明，GCN2 在响应控制细胞因子产生的脾树突状细胞和巨噬细胞中的凋亡细胞挑战时被激活，从而提出了依赖于 GCN2 的耐受诱导的新机制。在本提案中，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 及其下游效应器 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、向 T 细胞呈递抗原以及抑制适应性 T 细胞反应的能力中的作用 并在皮肤同种异体移植模型中诱导长期耐受。此外，我们将在小鼠模型中研究 GCN2 破坏对狼疮发展的影响，并将测试 GCN2 激活药物卤常酮在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原理。 ！

项目成果

Nuclear receptors, the aryl hydrocarbon receptor, and macrophage function.

• DOI: 10.1016/j.mam.2021.100942
• 发表时间: 2021-04
• 期刊: Molecular aspects of medicine
• 影响因子: 10.6
• 作者: Lamorte S;Shinde R;McGaha TL
• 通讯作者: McGaha TL

Dabrafenib Alters MDSC Differentiation and Function by Activation of GCN2.

Dabrafenib 通过激活 GCN2 改变 MDSC 分化和功能。

• DOI: 10.1158/2767-9764.crc-23-0376
• 发表时间: 2024
• 期刊: Cancer research communications
• 作者: Ciudad,MTeresa;Quevedo,Rene;Lamorte,Sara;Jin,Robbie;Nzirorera,Nadine;Koritzinsky,Marianne;McGaha,TracyL
• 通讯作者: McGaha,TracyL

Apoptotic cell responses in the splenic marginal zone: a paradigm for immunologic reactions to apoptotic antigens with implications for autoimmunity.

• DOI: 10.1111/imr.12382
• 发表时间: 2016-01
• 期刊: Immunological reviews
• 影响因子: 8.7
• 作者: McGaha TL;Karlsson MC
• 通讯作者: Karlsson MC