Celluar metabolism of Treg in the control of chronic inflammatory diseases

Treg细胞代谢在慢性炎症疾病控制中的作用

• 批准号: 391241754
• 负责人: Professor Dr. Tim Dominik Sparwasser
• 金额: --
• 依托单位: Institut für Medizinische Mikrobiologie und Hygiene
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/391241754?language=en
• 关键词: Celluar; metabolism; Treg; control; chronic

Cellular metabolism is becoming an emerging field of investigation in Immunology. For instance, it has been recently shown that a switch from oxidative phosphorylation to aerobic glycolysis in conventional T cells is a prerequisite for their proper activation. CD4+Foxp3+ regulatory T cells (Tregs) play a major role in the control of autoimmune and chronic inflammatory diseases. Current knowledge concerning the cellular metabolic characteristics of Tregs is limited and published studies are controversial. In this project, we will study the role of glucose and lipid metabolism in Treg homeostasis and function. First, we will compare the metabolic features of resting versus effector Tregs, and of Tregs from lymphoid versus non-lymphoid tissues. We will also analyze the effect of different types of chronic inflammation (such as high fat diet, cancer, autoimmunity or chronic infection) on Treg metabolism in specific tissues. Together, these data will allow us to obtain an integrative view of the metabolic features of Treg subsets according to their origin, activation state, tissue localization and inflammatory environment. We hypothesize that Tregs modify their metabolism depending on external cues and environment, providing an explanation for the existing controversies in the literature. Furthermore, we will use novel and unique models of conditional knock-out mice for genes that control critical hubs of glucose and lipid metabolism, to better understand how different aspects of glucose and lipid metabolism specifically in Tregs affect their biology in different tissues and thus their capacity to control inflammation. We will evaluate the influence of critical metabolic checkpoints for the development of spontaneous autoimmunity and other chronic inflammatory processes. Finally, in the last part of the project, we will make use of our conditional knock-out mice to narrow down the mechanism of action of metformin, a drug widely used in type 2 diabetic patients to regulate cellular metabolism. Because the drug has also an immuno-regulatory effect, we will assess whether part of its therapeutic action is due to a direct effect on Tregs. All in all, this project should increase our basic knowledge on the metabolism of Tregs, its impact on Treg homeostasis and function depending on environmental cues and last but not least, improve our understanding of the pathophysiology of major chronic immune-mediated diseases that are controlled by Tregs.

细胞代谢正在成为免疫学研究的一个新兴领域。例如，最近已经表明，在常规T细胞中从氧化磷酸化到有氧糖酵解的转变是其适当活化的先决条件。CD4+Foxp3+调节性T细胞（Treg）在自身免疫性疾病和慢性炎症性疾病的控制中起主要作用。目前关于TdR细胞代谢特征的知识有限，已发表的研究存在争议。在这个项目中，我们将研究糖和脂质代谢在Treg稳态和功能中的作用。首先，我们将比较静息与效应T细胞的代谢特征，以及淋巴组织与非淋巴组织的T细胞的代谢特征。我们还将分析不同类型的慢性炎症（如高脂饮食，癌症，自身免疫或慢性感染）对特定组织中Treg代谢的影响。总之，这些数据将使我们能够根据Treg亚群的起源、激活状态、组织定位和炎症环境获得Treg亚群代谢特征的综合视图。我们假设，TdR修改他们的代谢依赖于外部线索和环境，提供了一个解释现有的文献中的争议。此外，我们将使用新的和独特的条件性基因敲除小鼠模型来控制葡萄糖和脂质代谢的关键枢纽，以更好地了解葡萄糖和脂质代谢的不同方面如何影响它们在不同组织中的生物学，从而影响它们控制炎症的能力。我们将评估关键代谢检查点对自发性自身免疫和其他慢性炎症过程发展的影响。 最后，在该项目的最后部分，我们将利用条件性基因敲除小鼠来缩小二甲双胍的作用机制，二甲双胍是一种广泛用于2型糖尿病患者调节细胞代谢的药物。由于该药物也具有免疫调节作用，我们将评估其治疗作用的一部分是否是由于对T细胞的直接作用。总而言之，该项目应该增加我们对THBG代谢的基本知识，其对Treg稳态和功能的影响取决于环境线索，最后但并非最不重要的是，提高我们对THBG控制的主要慢性免疫介导疾病的病理生理学的理解。