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Endogenous and Dietary Sphingolipids as Modulators in Inflammatory Bowel Disease

Endogenous and Dietary Sphingolipids as Modulators in Inflammatory Bowel Disease
内源性和膳食鞘脂作为炎症性肠病的调节剂
批准号:
10222659
负责人:
JULIE D SABA
金额:
$36.34万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-06-15 至 2023-05-31
关键词:
AddressAffectAnabolismAnti-Inflammatory AgentsAntibodiesAntioxidantsBiochemicalCatabolismCell physiologyCell surfaceCellsChemicalsChemopreventive AgentChronicCitrobacter rodentiumCoculture TechniquesColitisColonColon CarcinomaComputing MethodologiesCrohn&aposs diseaseDevelopmentDiseaseEnterocytesEnzymesEpithelialExhibitsFoodFutureGeneticGlutathioneGoalsHuman ResourcesHuman bodyImmuneImmune responseImmunityIncidenceInfectionInflammationInflammatoryInflammatory Bowel DiseasesInjuryInterleukin-10IntestinesKnock-outKnockout MiceLeadLeukocytesLipidsLyaseMeasuresMediatingMedicalMetabolicMetabolismModelingMonitorMusOrganPathogenesisPathway interactionsPiroxicamPlantsPlatelet Activating FactorPlatelet Activating Factor ActivationPopulationProcessProductionPropertyProteinsReactive Oxygen SpeciesRiskRoleSPHK1 enzymeSTAT3 geneSamplingSignal PathwaySignal TransductionSourceSphingolipidsSphingosine-1-Phosphate ReceptorStimulusStressSymptomsT cell differentiationT cell therapyT-Cell ProliferationT-LymphocyteTestingTight JunctionsTimeTissuesUlcerative Colitisbasecarcinogenesiscarcinogenicitycolon cancer riskcomparativecytokinedietary sphingolipidsexperienceexperimental studygastrointestinal epitheliumgastrointestinal symptomgut homeostasisgut microbiomeimmune activationimmune functionin vitro Assayin vivoinflammatory disease of the intestineinhibitor/antagonistliquid chromatography mass spectrometrylymphocyte traffickingmetabolic profilemetabolomemetabolomicsmicrobialmicrobiome analysismicrobiome compositionmicrobiotanoveloxidant stressplatelet activating factor receptorpreventreceptorrecruitresponsesite-1 proteasesphingadienessphingosine 1-phosphatesphingosine-1-phosphate lyasetissue injurytool developmenttrafficking

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中文摘要
翻译
炎症性肠病(IBD)是一种由先天免疫和适应性免疫功能紊乱引起的慢性疾病
英文摘要
Inflammatory bowel disease (IBD) is a chronic condition caused by disruption of innate and adaptive immune mechanisms that normally maintain gut homeostasis. IBD also predisposes to the development of colitis- associated colon cancer (CAC). Elucidating mechanisms underlying the development and persistence of IBD could lead to new medical strategies to treat IBD and prevent CAC. Metabolism of sphingolipids is a major activity of gut epithelium that becomes dysregulated in inflamed tissues and is implicated in the pathogenesis of both IBD and CAC. Nonetheless, how sphingolipids mechanistically contribute to IBD development is poorly understood. Within enterocytes, sphingosine kinase 1 (SK1) can metabolize endogenous sphingolipids as well as mammalian dietary sphingolipids, leading to the formation of the bioactive molecule sphingosine-1- phosphate (S1P). S1P regulates lymphocyte trafficking and promotes inflammation and carcinogenesis by signaling through its receptors (S1PR1-5) and by activating STAT3 and NFκB. S1P lyase (SPL), an essential enzyme that is highly expressed in healthy enterocytes, irreversibly degrades S1P, keeping gut S1P levels low. However, SK1 is upregulated during inflammation, and SPL activity is hampered by oxidant stress. These changes result in accumulation of S1P. We generated tissue-specific SPLGutKO mice lacking SPL only in enterocytes. SPLGutKO mice have high gut S1P levels and provide a model for investigating S1P's role in colitis. Using both chemical and infectious models of colitis, we found that SPL inactivation in gut epithelium promotes colitis/CAC. We provide additional evidence that SPLGutKO mice exhibit alterations in immune cell trafficking to the gut, breach of the gut epithelial barrier, and profound changes in the metabolic profiles of gut tissues in the absence of an inflammatory stimulus. Specifically, we observed high levels of platelet activating factor (PAF) and depletion of glutathione (GSH) in SPLGutKO mouse intestines. PAF promotes leukocyte recruitment, activation and reactive oxygen species (ROS) formation through activation of the PAF receptor (PAFR). GSH is the main intracellular antioxidant needed to protect gut epithelium against ROS-mediated injury. Thus, the two key metabolic changes we observed in SPLGutKO mice could enhance oxidant stress while rendering the gut defenseless against that stress. Based on our findings, we hypothesize that sphingolipids influence the development of colitis by perturbing PAF and GSH metabolism, thereby altering immune cell trafficking and epithelial barrier integrity. To test this central hypothesis, we propose three Specific Aims: 1) Establish how sphingolipids perturb the gut metabolome; 2) Determine how sphingolipids facilitate immune cell trafficking to the gut; 3) Elucidate how sphingolipids compromise gut epithelial barrier integrity. By determining how sphingolipids influence gut metabolism of PAF and GSH, and testing causal relationships between sphingolipids, PAF, GSH, gut immune cell trafficking, and gut epithelial barrier functions, we will clarify how sphingolipid metabolism promotes colitis and, alternatively, how this pathway can be targeted to treat IBD.
期刊论文(5)
专著(0)
科研奖励(0)
会议论文
DOI: 10.1002/jimd.12238
发表时间: 2020-09
期刊: Journal of inherited metabolic disease
影响因子: 4.2
作者: [Zhao P, Liu ID, Hodgin JB, Benke PI, Selva J, Torta F, Wenk MR, Endrizzi JA, West O, Ou W, Tang E, Goh DL, Tay SK, Yap HK, Loh A, Weaver N, Sullivan B, Larson A, Cooper MA, Alhasan K, Alangari AA, Salim S, Gumus E, Chen K, Zenker M, Hildebrandt F, Saba JD]
通讯作者: Saba JD
DOI: 10.3390/ijms221910617
发表时间: 2021-09-30
期刊: International journal of molecular sciences
影响因子: 5.6
作者: [Spohner AK, Jakobi K, Trautmann S, Thomas D, Schumacher F, Kleuser B, Lütjohann D, El-Hindi K, Grösch S, Pfeilschifter J, Saba JD, Meyer Zu Heringdorf D]
通讯作者: Meyer Zu Heringdorf D
DOI: 10.1016/j.jbior.2018.09.004
发表时间: 2019-01
期刊: Advances in biological regulation
影响因子: --
作者: [Choi YJ, Saba JD]
通讯作者: Saba JD
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