Targeting the cellular fatty acid metabolism in intestinal infection and inflammation

针对肠道感染和炎症中的细胞脂肪酸代谢

• 批准号: 312920793
• 负责人: Privatdozent Dr. Matthias Lochner
• 金额: --
• 依托单位: Institut für Medizinische Mikrobiologie und Krankenhaushygiene
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/312920793?language=en
• 关键词: Targeting; cellular; fatty; acid; metabolism

Targeting the intracellular metabolism of immune cells is a promising emerging strategy for immunomodulation. Our previous work suggested that intracellular de novo fatty acid synthesis represents an important metabolic checkpoint for the reciprocal differentiation of Th17 versus regulatory T(reg) cells. The intestine serves as a major site for the induction of both Th17 and Treg cells, and the optimal regulation of the Th17/Treg balance is vital for normal intestinal homeostasis, resistance against infection and prevention from detrimental inflammation. It is the main objective of this proposal to study the impact of the two central processes of the cellular fatty acid metabolism, de novo fatty acid synthesis and fatty acid oxidation (FAO), on intestinal immune responses under in vivo conditions. To achieve this goal, we will use established as well as newly generated genetic mouse models that allow for the deletion of the key enzymes of fatty acid synthesis and FAO in specific immune- and non-immune cells, including T cells, innate lymphoid cells (ILC) and intestinal epithelial cells. This genetic approach will enable us to study the role of the cellular metabolism under infectious and inflammatory conditions in vivo, and to dissect the molecular and metabolic mechanisms by which the fatty acid metabolism influences immune cell fate and function in the intestine. In addition, we will assess the potential of pharmacological modulation of the fatty acid metabolism using specific inhibitors and translate these findings into the human system by analyzing the impact of the fatty acid metabolism in cells isolated from human intestinal tissues. The results of this work may not only lead to significant conceptual advances in the field of immunology, but will also offer an immediate therapeutic perspective for the treatment of gut-associated infectious and inflammatory diseases in humans

靶向免疫细胞的细胞内代谢是一种有前途的新兴免疫调节策略。我们以前的工作表明，细胞内从头脂肪酸的合成是一个重要的代谢检查点的相互分化的Th 17与调节性T（reg）细胞。肠道是诱导Th 17和Treg细胞的主要场所，Th 17/Treg平衡的最佳调节对于正常肠道稳态、抗感染和预防有害炎症至关重要。本提案的主要目的是研究体内条件下细胞脂肪酸代谢的两个中心过程（从头脂肪酸合成和脂肪酸氧化（FAO））对肠道免疫应答的影响。为了实现这一目标，我们将使用已建立的以及新生成的遗传小鼠模型，这些模型允许在特定的免疫细胞和非免疫细胞中删除脂肪酸合成和FAO的关键酶，包括T细胞，先天淋巴细胞（ILC）和肠上皮细胞。这种遗传方法将使我们能够研究体内感染和炎症条件下细胞代谢的作用，并剖析脂肪酸代谢影响肠道免疫细胞命运和功能的分子和代谢机制。此外，我们将评估使用特定抑制剂对脂肪酸代谢进行药理学调节的潜力，并通过分析从人肠道组织分离的细胞中脂肪酸代谢的影响将这些发现转化为人体系统。这项工作的结果不仅可能导致免疫学领域的重大概念进步，而且还将为人类肠道相关感染性和炎症性疾病的治疗提供直接的治疗前景

项目成果

Targeting cellular fatty acid synthesis limits T helper and innate lymphoid cell function during intestinal inflammation and infection

• DOI: 10.1038/s41385-020-0285-7
• 发表时间: 2020-04-30
• 期刊: MUCOSAL IMMUNOLOGY
• 影响因子: 8
• 作者: Mamareli, Panagiota;Kruse, Friederike;Lochner, Matthias
• 通讯作者: Lochner, Matthias

Etomoxir Actions on Regulatory and Memory T Cells Are Independent of Cpt1a-Mediated Fatty Acid Oxidation.

• DOI: 10.1016/j.cmet.2018.06.002
• 发表时间: 2018-09-04
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Raud B;Roy DG;Divakaruni AS;Tarasenko TN;Franke R;Ma EH;Samborska B;Hsieh WY;Wong AH;Stüve P;Arnold-Schrauf C;Guderian M;Lochner M;Rampertaap S;Romito K;Monsale J;Brönstrup M;Bensinger SJ;Murphy AN;McGuire PJ;Jones RG;Sparwasser T;Berod L
• 通讯作者: Berod L