Dissect and target Arginine-polyamine metabolic axis in T cell mediated inflammation and autoimmunity

剖析并靶向 T 细胞介导的炎症和自身免疫中的精氨酸-多胺代谢轴

基本信息

批准号：
10382328
负责人：
Ruoning Wang
金额：
$ 38.68万
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 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10382328
关键词：
Acids Age Aging Allergic Disease Amino Acids Anabolism Animal Model Anti-Inflammatory Agents Antigens Applied Research Arginine Arthritis Assimilations Autoimmune Autoimmune Diseases Autoimmunity Basic Science Binding Biochemical Reaction Bioenergetics Biological Availability Biological Models Biomass CD4 Positive T Lymphocytes Carbon Catabolism Cell Differentiation process Cell Proliferation Cells Cellular Metabolic Process Child Clinical Collagen Communicable Diseases Dependence Effector Cell Environment Experimental Autoimmune Encephalomyelitis Genes Genetic Growth Homeostasis Immune System Diseases Immune response Immune signaling Immunity Immunologic Surveillance In Vitro Inflammation Inflammatory Inflammatory Response Lead Location Mediating Metabolic Metabolic Pathway Metabolism Mission Modeling Molecular Multiple Sclerosis Mus National Institute of Allergy and Infectious Disease National Institute of General Medical Sciences Organism Ornithine Outcome Ovalbumin Pathogenesis Pathologic Pathway interactions Pharmacology Physiological Processes Polyamines Process Production Proliferating Protein Biosynthesis Public Health Receptor Activation Resources Rheumatoid Arthritis Signal Transduction Specificity T cell differentiation T cell response T-Cell Activation T-Cell Proliferation T-Cell Receptor T-Lymphocyte Testing Therapeutic Tissues c-myc Genes cell mediated immune response cost cytokine dietary dietary approach dietary manipulation dietary restriction effector T cell genetic approach immune function improved metabolomics mouse model new therapeutic target novel strategies novel therapeutic intervention novel therapeutics prevent programs reconstitution response therapy outcome transcription factor transcriptomics uptake

项目摘要

1 Summary: 2 CD4 T cell activation provides a model system for studying molecular mechanisms that coordinate a wide variety 3 of often competing physiological processes. When CD4 T cells encounter an antigen in the proper context, they 4 rapidly accumulate biomass, undergo extensive expansion, and differentiate into functional lineages that spe- 5 cialize on cytokine production. Robust and effective CD4 T cell-mediated immune responses require proper al- 6 location of metabolic resources through the central carbon metabolic pathways to sustain energetically costly 7 processes like growth, proliferation, and cytokine production. Also, ancillary metabolic pathways, such as amino 8 acid catabolism and polyamine (PA) biosynthesis, are critical to regulating T cell proliferation and inflammation. 9 The objective of this proposal is to understand how the arginine-polyamine metabolic axis is regulated during 10 T cell activation and ultimately contributes to inflammation and autoimmunity. Our lab recently revealed that the 11 transcription factor, c-Myc, controls an ancillary metabolic pathway that connects arginine (Arg) catabolism to 12 the biosynthesis of PAs, which are an essential class of polycationic metabolites ubiquitously present in all living 13 organisms. Unlike most other amino acids that are primarily used for anabolic protein synthesis during T cell 14 activation, most cellular Arg is catabolized and funneled into synthesizing PA (Arg-PA metabolic axis). Genetic 15 and pharmacological perturbation in the intracellular PA pool suppresses proliferation, suppresses TH1 and TH17 16 differentiation, but enhances iTreg differentiation. Hence, we hypothesize that the arginine-polyamine metabolic 17 axis orchestrates a metabolic checkpoint to optimize CD4 Teff cell proliferation and inflammatory re- 18 sponse. This checkpoint may be therapeutically exploited by polyamine blocking therapies. The aims of 19 this proposal are to 1) decipher the Arg-PA metabolic axis reprogramming and assess the impact of crucial 20 metabolic steps on Teff cells in the context of modulating Myc; 2) determine the outcomes of modulating Arg-PA 21 axis in regulating the effector function of T cells; 3) assess the contribution of PA de novo biosynthesis and the 22 PA salvage pathway to the intracellular PA-pool and T cell proliferation and effector function, and 4) develop and 23 test complementary enzymatic, genetic, and dietary strategies to exploit the Arg-PA axis to modulate inflamma- 24 tory response and autoimmunity in animal models of multiple sclerosis and rheumatoid arthritis. Collectively, the 25 expected outcomes of this project are significant as it will reveal the fundamental principles of the emerging 26 connections between cell metabolism, immune signaling, and T cell differentiation. These studies are critical to 27 developing novel approaches and therapeutic interventions that improve clinical outcomes of inflammatory and 28 autoimmune diseases.

1 总结： 2 CD4 T 细胞激活为研究协调多种分子机制提供了一个模型系统 3 经常相互竞争的生理过程。当 CD4 T 细胞在适当的环境中遇到抗原时，它们 4 快速积累生物量，经历广泛的扩张，并分化成特定的功能谱系 5 关注细胞因子的产生。强大而有效的 CD4 T 细胞介导的免疫反应需要适当的 6 通过中央碳代谢途径定位代谢资源以维持能源消耗生长、增殖和细胞因子产生等 7 个过程。此外，辅助代谢途径，例如氨基 8 酸分解代谢和多胺 (PA) 生物合成对于调节 T 细胞增殖和炎症至关重要。 9 该提案的目的是了解精氨酸-多胺代谢轴在 10 T 细胞激活并最终导致炎症和自身免疫。我们的实验室最近透露 11 转录因子 c-Myc 控制着将精氨酸 (Arg) 分解代谢与 12 PA 的生物合成，PA 是所有生物中普遍存在的一类重要的聚阳离子代谢物 13 种生物。与大多数其他主要用于 T 细胞合成代谢蛋白质合成的氨基酸不同 14 激活后，大多数细胞 Arg 被分解代谢并流入合成 PA（Arg-PA 代谢轴）。遗传 15 细胞内 PA 库的药理学扰动可抑制增殖、抑制 TH1 和 TH17 16 分化，但增强 iTreg 分化。因此，我们假设精氨酸-多胺代谢 17 轴协调代谢检查点以优化 CD4 Teff 细胞增殖和炎症再循环 18 响应。该检查点可通过多胺阻断疗法进行治疗性利用。的目标 19 该提案旨在 1) 破译 Arg-PA 代谢轴重编程并评估关键因素的影响在调节 Myc 的背景下 Teff 细胞的 20 个代谢步骤； 2) 确定调节Arg-PA的结果 21轴调节T细胞的效应功能； 3) 评估PA从头生物合成的贡献和 22 PA 挽救途径至细胞内 PA 池和 T 细胞增殖和效应器功能，以及 4) 开发和 23 测试互补的酶促、遗传和饮食策略，以利用 Arg-PA 轴调节炎症 24 多发性硬化症和类风湿性关节炎动物模型中的托里反应和自身免疫。总的来说，该项目的 25 项预期成果非常重要，因为它将揭示新兴技术的基本原则细胞代谢、免疫信号传导和 T 细胞分化之间的 26 个联系。这些研究对于 27 开发新方法和治疗干预措施，改善炎症和疾病的临床结果 28种自身免疫性疾病。