Decipher and target GABA metabolism and GABA receptor-mediated signaling in autoimmune diseases

破译并靶向自身免疫性疾病中的 GABA 代谢和 GABA 受体介导的信号传导

• 批准号: 10623380
• 负责人: Ruoning Wang
• 金额: $ 51.48万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-10 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623380
• 关键词: 4-Aminobutyrate aminotransferase; Ablation; Acceleration; Aging; Allergic Disease; Amino Acids; Animal Model; Antigens; Applied Research; Arginine; Autocrine Communication; Autoimmune Diseases; Autoimmunity; Basic Science; Binding; Biochemical Reaction; Butyrates; CD4 Positive T Lymphocytes; Carbon; Catabolism; Cell Differentiation process; Cell Lineage; Cell Proliferation; Cell Surface Receptors; Cells; Cellular Metabolic Process; Child; Citric Acid Cycle; Clinical; Communicable Diseases; Coupling; Deterioration; Disease; Effector Cell; Environment; Enzymes; Eragrostis; Experimental Autoimmune Encephalomyelitis; GABA Receptor; Gatekeeping; Gene Expression Profiling; Genes; Genetic; Genetic Models; Glutamates; Glutamine; Homeostasis; Human; IL27RA gene; Immune System Diseases; Immune response; Immune signaling; Immunity; Immunologic Surveillance; Inflammation; Inflammatory; Inflammatory Response; K/BxN model; Ligands; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mission; Molecular; Multiple Sclerosis; National Institute of Allergy and Infectious Disease; Neurotransmitters; Outcome; Pathogenesis; Pathway Analysis; Pathway interactions; Production; Proliferating; Public Health; Receptor Activation; Receptor Signaling; Regulatory T-Lymphocyte; Resources; Rheumatoid Arthritis; Role; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; Specificity; T cell differentiation; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-cell inflamed; Testing; Therapeutic; Tissues; Transaminases; autoimmune arthritis; cell mediated immune response; cost; cytokine; dietary approach; dietary restriction; effector T cell; evidence base; extracellular; gamma-Aminobutyric Acid; genetic approach; immune function; improved; in vivo; inflammatory modulation; metabolome; mouse model; new therapeutic target; novel strategies; novel therapeutic intervention; novel therapeutics; pharmacologic; presynaptic neurons; prevent; programs; receptor; receptor-mediated signaling; reconstitution; response; stable isotope; targeted treatment; therapy outcome; transcriptome

Summary: Properly allocating metabolic resources is crucial for mounting energetically costly T cell mediated-immune responses. In addition, cellular metabolic programs interact with cell-surface receptor signaling pathways by providing metabolites as ligands. This proposal aims to understand the role of γ-aminobutyric acid (GABA) in regulating T cell inflammation and explore the potential therapeutic value of targeting GABA in animal models of inflammatory and autoimmune diseases. An integrated analysis of the extracellular metabolome, stable isotope traced metabolic pathway analysis, and metabolic transcriptome revealed that GABA is one of the most abundant metabolites produced through glutamine and arginine catabolism in CD4+ T effector cells. Expressing 4-amino- butyrate aminotransferase (ABAT) funnels GABA as an anaplerotic substrate into the tricarboxylic acid cycle to maximize carbon allocation in promoting TH17 cell differentiation. By contrast, the absence of ABAT activities in iTreg cells enables GABA exporting to the extracellular environment and acting as an autocrine signaling metab- olite to suppress T cell inflammation. Accordingly, genetically or pharmacologically ablating ABAT activity in T cells suppresses inflammation in vivo. Conversely, genetically ablating GABA(A) receptor in T cells deteriorates inflammatory responses. Hence, we hypothesize that GABA functions as a metabolic and signaling gatekeeper in coordinating carbon assimilation and receptor signaling response to governing CD4 T effector cell proliferation and inflammatory response. The aims of this proposal are to 1) decipher the molecular and signaling mechanisms that control GABA metabolism in T cells; 2) determine the outcomes of modulating GABA metabolism and receptor signaling in regulating the effector function of T cells; 3) develop and test complementary enzymatic, genetic, and meta- bolic strategies to modulate inflammatory response and autoimmunity in animal models of multiple sclerosis and rheumatoid arthritis. Collectively, the expected outcomes of this project are significant as it will reveal the funda- mental principles of the emerging connections between cell metabolism, immune signaling, and T cell differenti- ation. These studies are critical to developing novel approaches and therapeutic interventions that improve clin- ical outcomes of inflammatory and autoimmune diseases.

总结： 正确分配代谢资源对于安装能量昂贵的T细胞介导的免疫系统至关重要。 应答此外，细胞代谢程序与细胞表面受体信号通路相互作用， 提供代谢物作为配体。本提案旨在了解γ-氨基丁酸（GABA）在 调节T细胞炎症，并探讨以GABA为靶点在动物模型中的潜在治疗价值。 炎症和自身免疫性疾病。细胞外代谢组、稳定同位素 跟踪代谢途径分析和代谢转录组显示，GABA是最丰富的 在CD 4 + T效应细胞中通过谷氨酰胺和精氨酸催化剂产生的代谢物。表达4-氨基- 丁酸氨基转移酶（ABAT）将GABA作为回补底物输送到三羧酸循环中， 最大化碳分配促进TH 17细胞分化。相比之下，由于缺乏减贫和可持续发展活动， iTreg细胞能够将GABA输出到细胞外环境，并作为自分泌信号转导代谢物发挥作用。 抑制T细胞炎症。因此，在T细胞中遗传或消除ABAT活性， 细胞抑制体内炎症。相反，基因切除T细胞中的GABA（A）受体会使T细胞的功能恶化， 炎症反应。 因此，我们假设GABA在协调碳代谢和信号传递中起着看门人的作用。 调节CD 4 T效应细胞增殖和炎症的同化和受体信号转导应答 反应该提案的目的是1）破译控制的分子和信号机制， T细胞中GABA代谢; 2）确定调节GABA代谢和受体信号传导的结果 在调节T细胞的效应器功能; 3）开发和测试互补的酶，遗传和Meta- 在多发性硬化动物模型中调节炎症反应和自身免疫的曲线策略， 类风湿关节炎总的来说，这个项目的预期成果是重要的，因为它将揭示基金- 细胞代谢、免疫信号传导和T细胞分化之间新兴联系的精神原则， 行动。这些研究对于开发新的方法和治疗干预措施，改善临床表现至关重要。 炎症和自身免疫性疾病的临床结果。