Gastrointestinal Cues Influence Metabolic Control of Regulatory T cell Function

胃肠道信号影响调节性 T 细胞功能的代谢控制

• 批准号: 10321303
• 负责人: Adebowale O Bamidele
• 金额: $ 14.43万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321303
• 关键词: Activities of Daily Living; Animal Model; Animals; Anions; Anti-Inflammatory Agents; Architecture; Biology; CD4 Positive T Lymphocytes; Cell physiology; Cells; Clinical; Clinical Trials; Colitis; Communication; Complex; Contact Inhibition; Crista ampullaris; Cues; Data; Development; Digestive System Disorders; Disease; Endoplasmic Reticulum; Environment; Experimental Models; FOXP3 gene; Fatty Acids; Functional disorder; Glycogen (Starch) Synthase; Goals; Health; Homeostasis; Human; IL2RA gene; Immune; Impairment; In Vitro; Individual; Inflammation; Inflammatory Bowel Diseases; Inositol; Intestines; Investigation; Knowledge; Lamina Propria; Lead; Light; Link; Mediating; Metabolic; Metabolic Control; Metabolism; Mitochondria; Molecular; Molecular Target; Nature; Oxidative Phosphorylation; Pathogenesis; Pathogenicity; Patients; Peripheral; Pharmacology; Phenotype; Pyruvate; Refractory; Regulation; Regulatory T-Lymphocyte; Research; Role; Self Tolerance; Shapes; Signal Transduction; Structure; TGFB1 gene; Testing; Therapeutic; Treg therapy; Voltage-Dependent Anion Channel; base; cytokine; design; effector T cell; extracellular; fatty acid oxidation; flexibility; gastrointestinal; glucose metabolism; glucose-regulated proteins; glycogen synthase kinase 3 beta; gut inflammation; in vivo; inflammatory milieu; inhibitor; innovation; interleukin-21; mouse model; murine colitis; novel; oxidation; peripheral blood; receptor; recruit; time use; tissue repair; transcription factor; treatment response; treatment strategy

PROJECT ABSTRACT Human inflammatory bowel disease (IBD) is characterized by inconsistent response to therapies and persistent activation of pathogenic effector CD4+ T cells implying regulatory T cell (Treg) dysfunction; however, the underlying mechanisms are poorly understood. Therefore, the OVERALL OBJECTIVE of this proposal is to elucidate the mechanisms by which gastrointestinal cues impact Treg metabolism and function with the therapeutic goal of defining pharmacological and adoptive Treg therapies to treat IBD. For the first time using complementary approaches, we have observed a defined mitochondrial ultrastructure (shape, cristae structure, and physical interaction with the endoplasmic reticulum [ER]) which correlated with Treg metabolic state. We are now poised to exploit how: i) mitochondrial ultrastructure and its associated metabolic state in Tregs suppress gut inflammation in various mouse models of experimental colitis; and ii) a breakdown in the regulation and function of mitochondrial ultrastructure can drive human IBD pathogenesis by analyzing Tregs from peripheral blood and lamina propria of IBD patients compared to relevant healthy individuals. Our preliminary data suggest that anti-inflammatory transforming growth factor beta 1 (TGF-β1) cytokine is a critical driver of mitochondria-ER contact (MERC) in Tregs via its associated molecular architecture, thus implicating intact MERC and subsequent pyruvate oxidation in Treg-mediated suppression of IBD. In our preliminary experimentations mimicking the proinflammatory milieu of IBD gastrointestinal tract, treatment of Tregs with proinflammatory cytokines impaired MERC and perturbed glucose metabolism, leading to excessive fatty acid oxidation as a compensatory mechanism in contrast to vehicle-treated Tregs (“proinflammatory cytokine- induced metabolic reprogramming”). Furthermore, we discovered that proinflammatory cytokine-induced metabolic reprogramming of Tregs was reversed by inhibiting the activity of glycogen synthase 3 beta (GSK3β) using a class of inhibitors currently being explored in clinical trials for other indications. Based on these novel observations, we formulated the CENTRAL HYPOTHESIS that TGF-β1 mediates mitochondria-ER contact that is essential for cellular metabolic homeostasis, Treg function, and suppression of IBD pathogenesis. The following independent SPECIFIC AIMS are designed to test three integrated hypotheses. First, we will directly test the hypothesis that TGF-β1 mediates MERC and consequently Treg function. Second, we will test the hypothesis that TGF-β1 potentiates mitochondrial pyruvate oxidation and consequently Treg function. Third, we will test the hypothesis that proinflammatory cytokines perpetuate IBD pathogenesis in vivo via MERC inhibition. We propose to utilize sophisticated approaches relevant to health and IBD pathophysiology to test this hypothesis. This proposal, which is technically and conceptually innovative, is also significant because it presents a novel concept in Treg biology and identifies new mechanisms for therapeutically optimizing Tregs, namely combining pharmacological and Treg-based therapies, to halt the refractory nature of IBD.

项目摘要 人类炎症性肠病 (IBD) 的特点是对治疗的反应不一致且持续存在 致病效应 CD4+ T 细胞的激活意味着调节性 T 细胞 (Treg) 功能障碍；然而， 根本机制尚不清楚。因此，该提案的总体目标是 阐明胃肠道信号影响 Treg 代谢和功能的机制 确定治疗 IBD 的药理学和过继性 Treg 疗法的治疗目标。第一次使用 补充方法，我们观察到了明确的线粒体超微结构（形状、嵴结构、 以及与内质网 [ER] 的物理相互作用，这与 Treg 代谢状态相关。我们 现在准备探索如何：i) Tregs 中的线粒体超微结构及其相关代谢状态 抑制各种实验性结肠炎小鼠模型的肠道炎症； ii) 细分 通过分析 Tregs 线粒体超微结构的调节和功能可以驱动人类 IBD 发病机制 与相关健康个体相比，IBD 患者的外周血和固有层。我们的 初步数据表明，抗炎转化生长因子β1（TGF-β1）细胞因子是一种关键的细胞因子。 Tregs 中线粒体-ER 接触 (MERC) 的驱动因素通过其相关的分子结构，因此暗示 Treg 介导的 IBD 抑制中完整的 MERC 和随后的丙酮酸氧化。在我们的初步 模拟 IBD 胃肠道促炎环境的实验，用 促炎细胞因子损害 MERC 并扰乱葡萄糖代谢，导致脂肪酸过多 与媒介物处理的 Tregs 相比，氧化作为一种​​补偿机制（“促炎细胞因子- 诱导代谢重编程”）。此外，我们发现促炎细胞因子诱导的 通过抑制糖原合酶 3 β (GSK3β) 的活性来逆转 Tregs 的代谢重编程 使用目前正在临床试验中探索的一类抑制剂用于其他适应症。根据这些小说 根据观察结果，我们提出了中心假设：TGF-β1 介导线粒体-ER 接触 这对于细胞代谢稳态、Treg 功能和抑制 IBD 发病机制至关重要。这 以下独立的具体目标旨在检验三个综合假设。首先我们直接 检验 TGF-β1 介导 MERC 进而介导 Treg 功能的假设。其次，我们将测试 假设 TGF-β1 增强线粒体丙酮酸氧化，从而增强 Treg 功能。第三， 我们将通过 MERC 检验促炎细胞因子在体内使 IBD 发病机制永久存在的假设 抑制。我们建议利用与健康和 IBD 病理生理学相关的复杂方法来测试 这个假设。这个提案在技术上和概念上都具有创新性，其意义也在于它 提出了 Treg 生物学的新概念，并确定了治疗优化 Tregs 的新机制， 即结合药物和基于 Treg 的疗法，以阻止 IBD 的难治性。