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： 2 CD4 T细胞激活提供了一个模型系统，用于研究分子机制，以互补种类繁多 3个经常竞争的生理过程。当CD4 T细胞在适当的情况下遇到抗原时， 4迅速积累生物量，经历广泛的扩张，并分化为功能谱系 5对细胞因子的产生进行cialize。强大而有效的CD4 T细胞介导的免疫反应需要适当的Al- 6通过中央碳代谢途径的代谢资源位置，以维持能量昂贵 7个过程，例如生长，增殖和细胞因子产生。另外，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如何调节精氨酸 - 聚丙胺代谢轴 10 T细胞激活，最终导致炎症和自身免疫性。我们的实验室最近透露了 11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 PA的生物合成，这是所有生物中普遍存在的多阳离子代谢物的必不可少的类别 13个生物。与大多数主要用于合成代谢蛋白合成过程中的其他氨基酸不同 14激活，大多数细胞ARG被分解代谢并漏斗到合成PA（ARG-PA代谢轴）中。遗传 15和细胞内PA池中的药理扰动抑制了增殖，抑制了TH1和TH17 16区分，但增强了ITREG分化。因此，我们假设精氨酸多胺代谢 17轴策划了一个代谢检查点，以优化CD4 TEFF细胞增殖和炎症性重复 18 Sponse。该检查点可以通过多胺阻断疗法来治疗。目的 19该提议是1）解密ARG-PA代谢轴重编程并评估关键的影响在调节MYC的背景下，Teff细胞上的20个代谢步骤； 2）确定调节ARG-PA的结果 21调节T细胞效应函数的轴； 3）评估新生生物合成和 22 PA打捞途径通往细胞内PA池和T细胞增殖和效应子功能，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关节炎动物模型中的保守反应和自身免疫性。集体， 25个该项目的预期结果很重要，因为它将揭示新兴的基本原则 26细胞代谢，免疫信号传导和T细胞分化之间的连接。这些研究对 27开发新的方法和治疗干预措施，以改善炎症和 28个自身免疫性疾病。