CD73 is a multi-functional protein that regulates liver injury
CD73 is a multi-functional protein that regulates liver injury
批准号:
9882993
负责人:
Natasha T Snider
金额:
$34.43万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-03-01 至 2022-02-28
关键词:
5&apos-NucleotidaseATF2 geneActive SitesAcuteAddressAdenosineAdenosine MonophosphateAlbuminsAlcoholsAnimalsAntibodiesApoptosisBindingBiochemicalBiologicalBiologyCardiovascular DiseasesCatalytic DomainCell surfaceCellsCessation of lifeChemicalsChronicChronic Hepatitis CCirrhosisClinicalCouplesDataDevelopmentDietDiseaseDisease ProgressionDown-RegulationEnzymesEstrogen receptor positiveEthanolEtiologyEventFibrosisGenesGenetic TranscriptionGoalsHepatocyteHigh Fat DietHomeostasisHumanImageIn VitroInflammationInjuryKnockout MiceLeukotrienesLigandsLipidsLiverLiver diseasesLoxP-flanked alleleMalignant NeoplasmsMessenger RNAMetabolicMetabolismMitochondriaModelingMolecularMusNamesNational Institute on Alcohol Abuse and AlcoholismPainPathologyPatientsPharmaceutical PreparationsPhosphorylationPlayPredispositionPrimary carcinoma of the liver cellsProtein IsoformsProteinsProteomicsRNA SplicingRecombinantsRegulationResearch PersonnelResistanceResourcesRoleSamplingSignal TransductionSiteSliceSolidStressSuggestionThromboxane B2TissuesTranscriptUp-RegulationVariantVirusWild Type MouseWorkbasechronic liver diseaseendoplasmic reticulum stressexperimental studyextracellularfeedingfootglycoproteomicsglycosylationhepatocellular injuryhepatocyte injuryimprovedin vivoinsightliver functionliver injuryloss of functionmRNA Precursormutantnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnovelproblem drinkerprotein functionreceptorresiliencescreeningtherapeutic target
中文摘要
摘要。
英文摘要
Abstract.
Their central importance to the synthetic, secretory and metabolic functions of the liver renders hepatocytes
particularly vulnerable to injury. Reinforcing hepatocyte resilience to damaging insults holds potential to block
liver disease progression at early stages, independent of etiology. To that end, ecto-5’-nucleotidase (CD73) is a
promising novel liver disease target, as it plays critical roles in multiple mouse liver injury models, and is
dysregulated in livers of patients with chronic liver diseases of multiple etiologies. The classical function of CD73
is metabolism of extracellular adenosine monophosphate (AMP) to adenosine. We found that global CD73-/- mice
are resistant to chemically-induced hepatocellular injury, an unexpected finding given that liver injury induces
near-complete loss of cell surface CD73 AMPase activity in wild-type mice. This points to alternative functions,
which is also supported by our identification of a novel, catalytically-inactive CD73 isoform (CD73S) in advanced
human liver disease. We observe differences in apoptosis-related signaling in primary hepatocytes expressing
the two different human CD73 isoforms. CD73 binds two bioactive lipids in vitro, suggesting that it may regulate
lipid homeostasis. Our central hypothesis is that non-enzymatic and alternative isoform-related mechanisms of
hepatocyte CD73 promote liver injury and disease progression. The hypothesis will be addressed via two specific
aims: (i) Define the non-enzymatic and isoform-specific functions of CD73 in hepatocytes and (ii) Examine the
in vivo and tissue-level mechanisms of hepatoprotection in the absence of CD73. Our approach for Aim 1 will
couple high throughput ligand screening, high content imaging, and proteomics with detailed biochemical,
molecular and cell-biological assessments to determine if CD73 is a lipid-sensing receptor or a regulator of ER
stress, and to determine the specific function of the non-catalytic CD73S variant in hepatocyte resistance to
stress. For Aim 2, we will examine liver-specific contributions of CD73 in vivo using two models of alcohol and
high fat diet-induced injury and our newly-generated liver-specific CD73-/- mice. We will utilize recombinant
enzyme in vivo and precision-cut liver slices to perform mechanistic rescue and loss-of-function studies. This
work will lead to a thorough integration of CD73 function in hepatocytes with the potential to yield novel
mechanistic approaches for hepatoprotection.
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科研奖励(0)
会议论文
Role of cellular metabolism in keratin variant-mediated liver disease progression
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批准号:8747902
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项目类别:
-
资助金额:$7.78万
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财政年份:2014
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负责人:Natasha T Snider
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依托单位:
Keratin sumoylation and its function during hepatocyte stress and liver disease
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批准号:8225803
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项目类别:
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资助金额:$10.82万
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财政年份:2011
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负责人:Natasha T Snider
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依托单位:
Keratin sumoylation and its function during hepatocyte stress and liver disease
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批准号:9111266
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项目类别:
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资助金额:$3.78万
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财政年份:2011
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负责人:Natasha T Snider
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依托单位:
Keratin sumoylation and its function during hepatocyte stress and liver disease
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批准号:8917199
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项目类别:
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资助金额:$15.16万
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财政年份:2011
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负责人:Natasha T Snider
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依托单位:
Keratin sumoylation and its function during hepatocyte stress and liver disease
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批准号:8522198
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项目类别:
-
资助金额:$10.87万
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财政年份:2011
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负责人:Natasha T Snider
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依托单位:
Keratin sumoylation and its function during hepatocyte stress and liver disease
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批准号:8333967
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项目类别:
-
资助金额:$10.87万
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财政年份:2011
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负责人:Natasha T Snider
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依托单位:
国内基金
海外基金
鼠伤寒沙门菌5'-nucleotidase在致病过程中的作用机制研究
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批准号:--
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项目类别:--
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资助金额:50万元
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批准年份:2023
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负责人:廖成水
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依托单位: