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Principal Investigator: Burcin Ekser
Organization: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
Fiscal Year: 2024
Award: $460,458
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Biliary liver diseases, such as primary sclerosing cholangitis (PSC), are characterized by the damage and
proliferation of cholangiocytes that are a key link between biliary injury and the subepithelial fibrosis, manifesting
chronic hepatobiliary injury that represents a major clinical challenge. Whereas biliary senescence and
inflammatory damage are crucial to the pathogenesis of biliary liver injury, there are significant gaps in
understanding the precise mechanisms of ductular reaction and liver fibrosis. Recent evidence demonstrates
stimulator of interferon genes (STING) as a mediator that promotes macrophage-stimulated liver inflammation
and fibrosis. In various cell types, STING is activated by cyclic GMP-AMP (cGAMP), whose synthesis is
catalyzed by cGAMP synthase (cGAS) in response to the aberrant cytosolic presence of double-stranded DNA
(dsDNA), including mitochondrial DNA (mtDNA). During the preliminary studies, we obtained exciting data
suggesting the following novel findings: 1) STING expression is increased in cholangiocytes, liver macrophages,
and hepatic stellate cells (HSCs) in livers of PSC patients; 2) cholangiocyte- and/or myeloid cell-specific STING
disruption alleviates ductular reaction and liver fibrosis during cholestasis; 3) while mtDNA is increased in
cholangiocytes from cholestatic mice, extracellular vesicles (EVs) isolated from human PSC cholangiocytes
promote macrophage activation in a manner involving STING; and 4) STING-driven macrophage factors
increase cholangiocyte expression of genes related to senescence-associated secretory phonotype (SASP) and
fibrosis. These findings point to a critical role for STING in regulating cholangiocyte damage and dysfunctional
cell-cell crosstalk during biliary liver injury. Based on these findings, we hypothesize that during cholestatic liver
injury, STING expression/activation is stimulated in cholangiocytes, liver macrophages, and HSCs through
autocrine and paracrine manners via EVs containing mtDNA cargo, which in turn results in dysfunctional cell-
cell crosstalk to enhance cholangiocyte SASP, macrophage/HSC activation, and consequent ductular reaction
and liver fibrosis. To test the central hypothesis, two Specific Aims will be persued. For Aim 1, experiments
involving novel mouse models have been proposed to determine the extent to which cholangiocyte-specific
STING disruption alleviates cholestatic-induced ductular reaction and liver fibrosis. Also, cell experiments will be
performed to determine the extent to which STING-driven cholangiocyte factors promote macrophage
proinflammatory activation and HSC fibrogenic activation. For Aim 2, experiments have been designed to
determine the extent to which myeloid cell-specific STING disruption alleviates cholestasis-induced ductular
reaction, cholangiocyte SASP, and liver fibrosis in mice. Also, cell experiments will be performed to evaluate the
extent to which STING-driven macrophage factors promote cholangiocyte SASP and HSC fibrogenic activation.
Successful completion of this project will fill knowledge gaps in biliary liver injury and provide the experimental
basis for innovative therapeutic strategies based on STING inhibition.
Terms: <Acceleration><Adipocytes><Adipose Cell><Adipose tissue><Autocrine Systems><Bile Acids><Bile Duct Obstruction><Biliary><Biliary Stasis><Bone-Derived Transforming Growth Factor><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cholestasis><Chronic><Clinical><Critical Paths><Critical Pathways><Cyclic GMP><Data><Development><Disease><Disorder><Double-Stranded DNA><Endothelial Cells><Fat Cells><Fatty Tissue><Fibrosis><Gene Action Regulation><Gene Activation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Guanosine Cyclic Monophosphate><Hepatic Cells><Hepatic Disorder><Hepatic Parenchymal Cell><Hepatic Stellate Cell><Hepatobiliary><Hepatocyte><Human><Immune><Immunes><Inflammation><Inflammatory><Injury><Injury to Liver><Innate Immunity><Intracellular Communication and Signaling><Ito Cell><Knowledge><Kupffer Cells><Link><Lipocytes><Liver><Liver Cells><Liver Fibrosis><Liver diseases><Macrophage><Macrophage Activation><Mature Lipocyte><Mature fat cell><Mediator><Mice><Mice Mammals><Milk Growth Factor><Mitochondria><Mitochondrial DNA><Modern Man><Molecular><Murine><Mus><Myeloid Cells><Mφ><NAFLD><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Organoids><Oxidative Stress><Pathogenesis><Pathology><Pathway interactions><Patients><Phenotype><Platelet Transforming Growth Factor><Play><Proliferating><Reaction><Research><Role><Secretin><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Stellate Sinusoidal Macrophage><Stimulator of Interferon Genes><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Testing><Therapeutic><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><adipose><autocrine><bile obstruction><bile occlusion><biological signal transduction><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><cGMP><cell type><cholangiocyte><cholestatic diseases><cholestatic disorder><cholestatic liver disease><cholestatic liver disorder><cholestatic syndromes><cyclic GMP-AMP synthase/STING><design><designing><developmental><ds-DNA><dsDNA><experiment><experimental research><experimental study><experiments><extracellular vesicles><fibrotic liver><hepatic body system><hepatic damage><hepatic disease><hepatic fibrosis><hepatic inflammation><hepatic injury><hepatic organ system><hepatopathy><inflamed liver><injuries><innovate><innovation><innovative><insight><liver damage><liver disorder><liver inflammation><liver injury><liver macrophage><mitochondrial><mouse model><mtDNA><murine model><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><non-alcohol fatty liver disease><non-alcoholic fatty liver disease><non-alcoholic liver disease><nonalcoholic fatty liver disease><novel><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><paracrine><pathway><primary sclerosing cholangitis><response><senescence><senescence associated secretome><senescence associated secretory phenotype><senescent><social role><validation studies><white adipose tissue><yellow adipose tissue>