Metabolic programming in TH17 cell differentiation

TH17 细胞分化中的代谢编程

基本信息

批准号：
9225170
负责人：
Ruoning Wang
金额：
$ 37.38万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-15 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9225170
关键词：
Acute Animal Model Anti-Inflammatory Agents Anti-inflammatory Antigens Area Autoimmune Diseases Autoimmune Process Autoimmunity Automobile Driving Binding Biochemical Biochemical Reaction Bromodomain CD4 Positive T Lymphocytes Cell Differentiation process Cell Lineage Cells Cellular Metabolic Process Chromatin Clinical Clonal Expansion Complex Cytokine Signaling Dependency Development Enzymes Event Experimental Autoimmune Encephalomyelitis FRAP1 gene Fatty Acids Fumarates Genetic Genetic Models Genetic Polymorphism Genomics Glucose Glutamine Glycolysis Goals Helper-Inducer T-Lymphocyte Human Immune Immune System Diseases Immune response Immune system In Vitro Inflammation Inflammatory Interleukin-6 Intervention Link Mediating Metabolic Metabolic Pathway Metabolism Molecular Multiple Sclerosis Nutrient Oral Pathogenesis Pathologic Permeability Pharmacology Play Predisposition Property Proteins Proto-Oncogene Proteins c-myc Proto-Oncogenes Psoriasis Pyruvate Kinase Regulation Regulatory T-Lymphocyte Research Role Signal Pathway Signal Transduction Succinate Dehydrogenase T cell differentiation T cell regulation T-Lymphocyte Testing Therapeutic Therapeutic Effect Tissues Translating Work addiction aerobic glycolysis animal data c-myc Genes cytokine fatty acid oxidation genetic approach hypoxia inducible factor 1 immune function immunoregulation in vivo insight interleukin-23 mouse model new therapeutic target novel therapeutic intervention pathogen pre-clinical preference programs public health relevance reconstitution response therapy outcome transcription factor transcriptome

项目摘要

DESCRIPTION (provided by applicant): When naive T cells encounter foreign antigen along with proper co-stimulation and cytokines, they undergo rapid and extensive clonal expansion and differentiate into specific lineages. Two closely related lineages in CD4+ T cells are TH17 cells, which promote inflammation, and Treg, which dampen immune responses. Recent work from us and others has shown that T cell metabolic pathways are tightly and ubiquitously linked with T cell differentiation and immune functions, implicating a great potential for modulating T cell immune responses through targeting metabolic processes. Recent work from us and others indicated a preference on glycolysis during TH17 differentiation but not during iTreg differentiation, and suggests that such metabolic preferences play a role in driving cell fate towards TH17 or iTreg. These studies indicate the presence of T cell lineage- specific metabolic programs and cell intrinsic mechanisms of metabolic regulation of T cell differentiation. However, the complete profile of T cell lineage-specific metabolic programs, the regulatory mechanisms of metabolic reprogramming during T cell differentiation and the potential therapeutic application of targeting T cell metabolic programs remain elusive. Our studies to date have implicated the transcription factor Myc as one of the key "nodes" coordinately regulating TH17 cell metabolism and differentiation. We therefore hypothesize that the Myc-mediated metabolic reprogramming and metabolic checkpoint fuels TH17 differentiation and represents a novel therapeutic target of autoimmune diseases. Our goals follow directly from this hypothesis and we propose to apply biochemical, cellular and genetic approaches to investigate the role of Myc and metabolic reprogramming in regulating T cell differentiation. Specifically, we will: a) determine the TH17 lineage-specific metabolic reprogramming, metabolic addiction and the role of Myc in regulating TH17 metabolism and differentiation (aim 1); b) elucidate the dynamic interplay among Myc, TORC1 and HIF1� in mediating a metabolic checkpoint in TH17 differentiation (aim 2); and c) assess the metabolic program as a novel therapeutic target for TH17-mediated autoimmune diseases (aim 3). Our proposal employs genetic models and metabolic approaches and focuses on TH17 cells as a starting point to dissect how the metabolic pathway regulation impacts immune responses in physio-pathological settings. The insights generated from this study will reveal fundamental interplays between signaling pathways and metabolic pathways in the immune system. These studies of immune metabolism may identify novel therapeutic intervention strategies for inflammatory and autoimmune diseases.

描述（由申请人提供）：当初始 T 细胞遇到外来抗原以及适当的共刺激和细胞因子时，它们会经历快速和广泛的克隆扩增并分化成特定的谱系，CD4+ T 细胞中两个密切相关的谱系是 TH17 细胞。我们和其他人最近的研究表明，T 细胞代谢途径与 T 细胞分化和免疫功能密切相关，并且具有巨大的调节潜力。我们和其他人最近的研究表明，在 TH17 分化过程中对糖酵解有偏好，但在 iTreg 分化过程中没有，并且表明这种代谢偏好在驱动细胞向 TH17 或 iTreg 方向发展方面发挥着作用。 T 细胞谱系特异性代谢程序的存在和 T 细胞分化代谢调节的细胞内在机制，T 细胞谱系特异性代谢程序的完整概况、T 细胞分化过程中代谢重编程的调节机制以及潜在的治疗方法。应用迄今为止，我们的研究表明转录因子 Myc 是协调调节 TH17 细胞代谢和分化的关键“节点”之一，因此我们发现 Myc 介导的代谢重编程和代谢检查点促进了 TH17 分化。并代表了自身免疫性疾病的新治疗靶点，我们的目标直接源于这一假设，我们建议应用生化、细胞和遗传学方法来研究 Myc 和代谢重编程在调节 T 细胞分化中的作用。具体来说，我们将：a) 确定 TH17 谱系特异性代谢重编程、代谢成瘾以及 Myc 在调节 TH17 代谢和分化中的作用（目标 1）；b) 阐明 Myc、TORC1 和 HIF1 在介导 a 过程中的动态相互作用。 TH17 分化中的代谢检查点（目标 2）；以及 c) 评估代谢程序作为 TH17 介导的自身免疫性疾病的新治疗靶点（目标 3）。我们的建议采用遗传模型和代谢方法，并以 TH17 细胞为起点，剖析代谢途径调节如何影响生理病理环境中的免疫反应，本研究产生的见解将揭示信号途径和代谢途径之间的基本相互作用。这些免疫代谢研究可能会确定针对炎症和自身免疫性疾病的新治疗干预策略。