The ATP Citrate Lyase (ACLY) as regulator of gut T cell immunometabolism in inflammatory bowel diseases.

ATP 柠檬酸裂解酶 (ACLY) 作为炎症性肠病肠道 T 细胞免疫代谢的调节剂。

• 批准号: 511510453
• 负责人: Privatdozentin Dr. Imke Atreya, Ph.D.
• 金额: --
• 依托单位: Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/511510453?language=en
• 关键词: ATP; Citrate; Lyase; ACLY; regulator

Inflammatory bowel diseases (IBD) affect nearly 8 million people worldwide and are characterized by chronically remitting episodes of severe gastrointestinal symptoms, which negatively impact on the quality of life and working ability of IBD patients and, overtime, can trigger the development of colorectal cancer. Thus, it is absolutely desirable to achieve a stable therapeutic control of the inflammatory process. However, despite the very successful introduction of new biological agents during the last three decades, which specifically interfere with the immunopathogenesis of IBD, still approximately 40% of IBD patients do not achieve a satisfactory and long-lasting response to the clinically established therapeutic regimens. In view of the resulting challenge to further optimize IBD therapy, it seems attractive to widen the current spectrum of immune cell-modulating factors of relevance in intestinal inflammation that can be addressed therapeutically. In this context, our project will focus on the process of immunometabolic T cell regulation in the inflamed mucosa of IBD patients, which still remains incompletely defined and potentially offers a broad spectrum of not yet fully considered therapeutic target structures. In particular, we are interested in the metabolic enzyme ATP Citrate Lyase (ACLY), which catalyzes the formation of acetyl-coenzyme A from mitochondria-released citrate and thereby impacts on important regulatory mechanisms in activated and expanding T cells. Our preliminary and unpublished analyses already indicated an inflammation-triggered downregulation of ACLY protein expression in the intestinal immune cell compartment in murine colitis and IBD patients and demonstrated a decreased colitis-inducing capacity of ACLY-deficient CD4+ T cells in vivo. Moreover, the short-chain fatty acid butyrate could be identified as a potent negative regulator of ACLY expression in CD4+ T cells. Based on the already acquired data, we aim on the experimental validation of the following hypothesis: By downregulating ACLY activity in lamina propria T cells, the mucosal immune system counteracts intestinal inflammation. Therapeutic enhancement of this process, for instance by increasing the availability of butyrate in the intestinal lamina propria or by targeting ACLY-initiated downstream signaling cascades in T cells, might thus promote resolution of inflammation in IBD. Moreover, following the presented work programme, we intend to identify the exact mechanisms through which the metabolic function of ACLY is translated into its immunomodulating capacity and, thereby, we hope to pave the way for innovative therapeutic strategies targeting T cell immunometabolism in IBD by interfering with ACLY function.

炎症性肠病（IBD）影响全球近800万人，其特征是严重胃肠道症状的慢性缓解发作，这对IBD患者的生活质量和工作能力产生负面影响，并且随着时间的推移，可能引发结直肠癌的发展。因此，实现对炎症过程的稳定治疗控制是绝对可取的。然而，尽管在过去三十年中非常成功地引入了新的生物制剂，专门干扰IBD的免疫发病机制，但仍有大约40%的IBD患者对临床建立的治疗方案没有达到满意和持久的反应。鉴于进一步优化IBD治疗所面临的挑战，扩大目前肠道炎症相关免疫细胞调节因子的范围似乎很有吸引力，这些因子可以通过治疗来解决。在此背景下，我们的项目将重点关注IBD患者炎症粘膜中免疫代谢T细胞调节的过程，这一过程仍未完全定义，并可能提供尚未充分考虑的治疗靶结构的广谱。特别是，我们对代谢酶ATP柠檬酸裂解酶（ACLY）感兴趣，它催化线粒体释放的柠檬酸盐形成乙酰辅酶A，从而影响激活和扩张T细胞的重要调节机制。我们的初步和未发表的分析已经表明，在小鼠结肠炎和IBD患者中，炎症引发的肠道免疫细胞区ACLY蛋白表达下调，并证明体内ACLY缺陷CD4+ T细胞诱导结肠炎的能力下降。此外，短链脂肪酸丁酸盐可以被鉴定为CD4+ T细胞中ACLY表达的有效负调节因子。基于已获得的数据，我们旨在通过实验验证以下假设：粘膜免疫系统通过下调固有层T细胞ACLY活性来抵消肠道炎症。通过治疗增强这一过程，例如增加肠固有层丁酸盐的可用性或靶向acly启动的T细胞下游信号级联，可能会促进IBD炎症的消退。此外，根据提出的工作计划，我们打算确定ACLY的代谢功能转化为其免疫调节能力的确切机制，因此，我们希望为通过干扰ACLY功能靶向IBD中T细胞免疫代谢的创新治疗策略铺平道路。