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

基本信息

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
项目类别：
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

项目摘要

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.

概括：正确分配代谢资源对于实现能量消耗巨大的 T 细胞介导的免疫至关重要此外，细胞代谢程序通过以下方式与细胞表面受体信号通路相互作用。提供代谢物作为配体。该提案旨在了解 γ-氨基丁酸 (GABA) 在中的作用。调节T细胞炎症并探索靶向GABA在动物模型中的潜在治疗价值炎症和自身免疫性疾病的细胞外代谢组、稳定同位素的综合分析。追踪代谢途径分析和代谢转录组显示 GABA 是最丰富的代谢途径之一表达 4-amino- 的 CD4+ T 效应细胞中通过谷氨酰胺和精氨酸分解代谢产生的代谢物。丁酸转氨酶 (ABAT) 将 GABA 作为回补底物输送到三羧酸循环中最大化碳分配以促进 TH17 细胞分化。相比之下，ABAT 活性的缺乏。 iTreg 细胞能够将 GABA 输出到细胞外环境并充当自分泌信号代谢抗体 olite 抑制 T 细胞炎症，从而通过遗传或药理学消除 T 细胞中的 ABAT 活性。细胞离线抑制炎症，T 细胞中基因消除的 GABA(A) 受体恶化。炎症反应。因此，我们研究 GABA 在协调碳中作为代谢和信号传导守门人的功能。同化和受体信号传导反应控制 CD4 T 效应细胞增殖和炎症该提案的目的是 1) 破译控制的分子和信号机制。 T 细胞中的 GABA 代谢；2) 确定调节 GABA 代谢和受体信号传导的结果调节 T 细胞的效应功能；3) 开发和测试互补的酶、遗传和元功能在多发性硬化症动物模型中调节炎症反应和自身免疫的代谢策略总的来说，该项目的预期成果非常重要，因为它将揭示其基本原理。细胞代谢、免疫信号传导和 T 细胞分化之间新兴联系的心理原理这些研究对于开发改善临床的新方法和治疗干预措施至关重要。炎症和自身免疫性疾病的临床结果。