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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：
10116883
负责人：
Ruoning Wang
金额：
$ 40.03万
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/10116883
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摘要： CD4T细胞活化为研究协调多种分子机制的分子机制提供了一个模型系统 3经常是相互竞争的生理过程。当CD4T细胞在适当的环境中遇到抗原时，它们 4迅速积累生物量，经历广泛的扩张，并分化为功能谱系，从而加速- 5注重细胞因子的产生。强大而有效的CD4T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，以维持高能量成本生长、增殖和细胞因子产生等7个过程。此外，辅助代谢途径，如氨基 8酸分解代谢和多胺(PA)的生物合成是调节T细胞增殖和炎症的关键。 9这项建议的目的是了解精氨酸-多胺代谢轴是如何在 10T细胞被激活，最终导致炎症和自身免疫。我们的实验室最近发现，转录因子c-Myc控制着连接精氨酸(Arg)分解代谢的辅助代谢途径。 12多胺的生物合成，这是普遍存在于所有生物中的一类重要的多阳离子代谢物。 13种生物。与大多数其他氨基酸不同，大多数氨基酸主要用于T细胞合成合成蛋白质 14激活后，大多数细胞内的Arg被分解代谢并进入合成PA(Arg-PA代谢轴)。遗传 15和细胞内PA池的药物扰动抑制增殖，抑制TH1和TH17 16分化，但会增强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CD 4 T细胞的增殖和炎症再循环 18个自助人。这一检查点可能会被多胺阻断疗法利用。的目标是 19这项建议是为了1)破译Arg-PA代谢轴重新编程并评估关键的调节Myc的TJeff细胞上的20个代谢步骤；2)决定调节Arg-PA的结果 21轴调节T细胞的效应器功能；3)评估PA从头合成的贡献和 22 PA挽救途径到细胞内PA池和T细胞的增殖和效应功能，以及4)发展和 23测试互补的酶、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的保守性反应和自身免疫。总体而言，这一项目的预期成果意义重大，因为它将揭示新兴市场的基本原则 26细胞代谢、免疫信号和T细胞分化之间的联系。这些研究对于 27开发新的方法和治疗干预措施，以改善炎症性和非传染性疾病的临床结果 28种自身免疫性疾病。