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

摘要： 合理分配代谢资源是建立高能量代价T细胞介导免疫的关键 回应。此外，细胞代谢程序通过与细胞表面受体信号通路相互作用 以配体的形式提供代谢物。该建议旨在了解γ-氨基丁酸在 调节T细胞炎症及探讨靶向GABA对实验性脑出血动物模型的治疗价值 炎症性和自身免疫性疾病。胞外代谢组、稳定同位素的综合分析 跟踪代谢途径分析和代谢转录组显示，GABA是最丰富的 CD4T效应细胞通过谷氨酰胺和精氨酸分解代谢产生的代谢物。表达4-氨基- 丁酸氨基转移酶(ABAT)将GABA作为一种逆转录底物进入三羧酸循环，以 最大限度地促进TH17细胞分化的碳分配。与之形成对比的是，在中国没有戒烟活动。 ITreg细胞能够将GABA输出到细胞外环境，并作为自分泌信号传递Metab- 石英石可抑制T细胞炎症。因此，从基因或药物上消融T细胞中的ABAT活性 细胞在体内抑制炎症。相反，通过基因去除T细胞中的GABA(A)受体会恶化 炎症反应。 因此，我们假设GABA在协调碳方面起代谢和信号守门人的作用。 调节CD4T效应细胞增殖和炎症的同化和受体信号反应 回应。这项提议的目的是：1)破译控制分子和信号机制 T细胞的GABA代谢；2)决定调节GABA代谢和受体信号转导的结果 在调节T细胞的效应器功能方面；3)开发和测试互补的酶、遗传和代谢- 多发性硬化症动物模型中调节炎症反应和自身免疫的药物策略 类风湿关节炎。总体而言，该项目的预期成果意义重大，因为它将揭示基金会-- 细胞代谢、免疫信号和T细胞差异之间新出现的联系的心理原理 阿齐兹。这些研究对于开发新的方法和治疗干预措施以改善临床症状至关重要。 炎症性和自身免疫性疾病的临床后果。

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.