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

简介:

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.