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

1摘要： 2 CD 4 T细胞活化提供了一个模型系统，用于研究协调多种 3、经常竞争的生理过程。当CD 4 T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，并分化成功能谱系， 5细胞因子的产生。稳健和有效的CD 4 T细胞介导的免疫应答需要适当的免疫调节。 6通过中心碳代谢途径定位代谢资源，以维持能量消耗 7个过程，如生长、增殖和细胞因子产生。此外，辅助代谢途径，如氨基 8酸催化剂和多胺（PA）生物合成，对调节T细胞增殖和炎症至关重要。 9本提案的目的是了解在代谢过程中，精氨酸-多胺代谢轴是如何调节的。 10 T细胞活化并最终导致炎症和自身免疫。我们的实验室最近发现， 11转录因子，c-Myc，控制一个辅助代谢途径，连接精氨酸（Arg）催化剂， PAs的生物合成，PAs是普遍存在于所有生物体中的一类重要的聚阳离子代谢物， 13个生物体。与大多数其他氨基酸不同，它们主要用于T细胞合成蛋白质。 14活化时，大多数细胞Arg被分解代谢并汇集成合成PA（Arg-PA代谢轴）。遗传 15和细胞内PA池中的药理学扰动抑制增殖，抑制TH 1和TH 17 16分化，但增强iTreg分化。因此，我们假设，在代谢过程中， 17轴协调代谢检查点，以优化CD 4 Teff细胞增殖和炎症反应。 18 sponse.该检查点可通过多胺阻断疗法在治疗上加以利用。的目的 19这项建议是1）破译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轴在调节T细胞效应功能中的作用; 3）评估PA从头生物合成的贡献和PA在T细胞中的作用。 22 PA补救途径对细胞内PA池和T细胞增殖和效应器功能的影响，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， 多发性硬化症和类风湿性关节炎动物模型中的Tory反应和自身免疫。统称 该项目的25项预期成果意义重大，因为它将揭示新兴的 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，改善炎症和 28种自身免疫性疾病

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.