36Characterization of GPCRs involved in inflammatory lipid signaling in vivoWe and others have shown that circulating small molecule metabolites di-rectly control states of inflammation and immunity. Small molecule metabolites in the blood include hundreds of bio-active lipid molecules, including oxy-lipins, eicosanoids, phosphatidic acids and others, that directly regulate cells of the innate and adaptive immune system by signaling through specific G-protein coupled receptors (GPCR) and nuclear receptors (NR). Regarding human dis-ease, perturbations in lipid metabolism and lipid metabolite signaling are im-plicated in the onset of inflammatory disorders, including Alzheimer’s Disease, cancer and many others. Notably, in the immune system the cause and effect of changes to metabolism and the effector metabolites involved are incompletely understood, and much remains to be learned regarding identification and char-acterization of novel small molecule metabolites that regulate immunity and inflammation in vivo.In the Laboratory of Inflammatory Immune Metabolism we are assessing the functional interplay between levels of bio-active lipids in the blood or tissues and corresponding immune signatures (e.g. cytokines, immune cell populations and expression of immune signature genes/proteins) with disease pathology, by studying in vivo genetic models of Alzheimer’s Disease and other inflammatory disorders. Notably, for many bio-active metabolites the precise signaling recep-tor targets are still unknown or are poorly characterized for their specific role in meditating inflammation in vivo. To dissect the functional role that bio-active lipids play in driving or resolving inflammation in vivo, we are using an innova-tive auxin-inducible degron (AID) system for targeted protein depletion of spe-cific GPCR and NR involved in propagating lipid metabolite signals in specific cell types, including inflammatory neutrophils and other innate immune cells. By assessing the effect of deleting specific lipid metabolite receptors we expect to identify new targets for modulation of immune-metabolism. Collaborative labo-ratories on this project include the Laboratory for Transcriptional Regulation.Figure: Simplified scheme of inducible disrup-tion of GPCR in vivo using degron systemWe inserted an AID (auxin-inducible degron) sequence at the 3’ prime region of candidate receptors. These AID-tagged receptor proteins undergo degradation upon expression of exogenous TIR-1 E3 ubiquitin ligase and auxin. The expression of TIR-1 in the Rosa locus is controlled by cell type specific Cre mouse (Ly6G-cre for neutrophil-specific targeting, CD4-cre for T cell, etc.) Degradation occurs only upon intraperitoneal injection of auxin, allowing for the depletion of the target recep-tor at our discretion, unlike conditional gene targeting. Using this system, we will address how lipids regulate neutrophil homeostasis or T cell functions via GPCR signaling.Recent Major PublicationsTakahashi M, Lio CJ, Campeau A, Steger M, Ay F, Mann M, Gonzalez DJ, Jain M, Sharma S. The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFN-β pathway. Nat Immunol 22, 485-496 (2021)Dhanwani R, Takahashi M, Mathews IT, Lenzi C, Ro-manov A Watrous JD, Pieters B, Banerjee S, Hedrick CC, Benedict CA, Linden J, Nilsson R, Jain M, Sharma S. Cel-lular sensing of extracellular purine nucleosides triggers an innate immune response. Sci Adv 6, eaba3688 (2020)Watrous JD, Niiranen TJ, Lagerborg KA, Henglin M, Xu YJ, Rong J, Sharma S, Vasan RS, Larson MG, Armando A, Mora S, Quehenberger O, Dennis EA, Cheng S, Jain M. Directed non-targeted mass spectrometry and chemi-cal networking for discovery of eicosanoids and related oxylipins. Cell Chem Biol 26, 433-442.e4 (2019)Invited presentationsSharma S. “Bio-active lipid metabolites regulate clinical cancer immunotherapy outcomes” Immunology Center of Georgia Seminar Series (Augusta, USA) April 2024Sharma S. “Bio-active lipid metabolites regulate in-flammation and immunity in cancer and Alzheimer’s Disease” RIKEN IMS Annual Retreat (Yokohama, Japan) March 2024Sharma S. “Sex Differences in Alzheimer’s Disease and other Inflammatory Syndromes” Tremblay-Jacobs Sym-posium on Autoimmunity (La Jolla, USA) February 2024Sharma S. “Lipid metabolites, cancer immunotherapy, and immune-related adverse events” UCSD-Moores Cancer Center Solid Tumor Therapeutics Symposium (La Jolla, USA) January 2024Laboratory for Inflammatory Immune MetabolismTeam Leader: Sonia Sharma
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