Dysregulation of Epithelial Metabolism and Regeneration by Sulfite Exposure in Pediatric Ulcerative Colitis
小儿溃疡性结肠炎亚硫酸盐暴露导致上皮代谢和再生失调
基本信息
- 批准号:10722914
- 负责人:
- 金额:$ 9.15万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:Adverse effectsAffectAmericanAnimal ModelAwardBar CodesBiologyBiopsyCell Differentiation processCell RespirationCellsCellular Metabolic ProcessChildChild NutritionChildhoodChromatinColitisColonColonic inflammationComplexConsumptionDataDefectDeveloped CountriesDietDietary FactorsDigestive System DisordersDiseaseDisease ManagementDisease modelDrug Metabolic DetoxicationEnvironmentEnvironmental Risk FactorEpitheliumExcisionExposure toFood PreservativesFoundationsFundingFutureGenesGoalsHealthHomeostasisHumanImpairmentIncidenceInflammatory Bowel DiseasesIngestionIntakeIntestinesMaintenanceMetabolicMetabolismMitochondriaMitochondrial DNAModelingMusMutationNatural regenerationOrganoidsOutcomePathway interactionsPatientsPediatric ulcerative colitisPhasePhenotypePhysiologicalPlayPredispositionPrevalencePublishingRecoveryResearchResearch PersonnelRoleSafetySamplingScienceShapesSignal TransductionSiteSourceSulfitesSulfurTissuesTrainingUlcerative ColitisUnited States National Institutes of HealthVariantWorkbiobankcareerdietarydisorder controlepigenomeepigenomicsepithelial injuryepithelial repairepithelial stem cellfeedinggastrointestinal epitheliumgut microbiotahuman tissuein vivoinhibitorinnovationintestinal barrierintestinal epitheliummitochondrial DNA mutationmitochondrial dysfunctionmitochondrial metabolismmolybdenum cofactormouse modelnutritionpediatric patientsprogramsregenerativeresponseself-renewalskillsstem cell derived tissuesstem cell differentiationstem cellstranscriptomicswestern diet
项目摘要
PROJECT SUMMARY
The prevalence of ulcerative colitis (UC) in children continues to increase yearly. Recent evidence in pediatric
UC patients showed significant mitochondrial impairment in the colon tissues. This is important as optimal
mitochondrial activity is required for the solemn function of colonic stem cells that replenish the physical barrier
of the colon epithelium. Since patients are constantly exposed to environmental factors such as diet, it is critical
to reveal the dietary factors that influence mitochondrial function in the colon epithelium as they would be vital in
the management of UC in children. Sulfites are endogenous products of several sulfur-containing compounds,
and they are also ubiquitous in our diets as preservatives. My preliminary data in colon organoids derived from
pediatric patients showed a detrimental role of sulfite on mitochondrial metabolism and differentiation, with worse
metabolic outcomes in samples from pediatric UC patients. My analysis of transcriptomic data from 206 children
with UC showed that the Mocs1 gene required for downstream clearance of sulfites in the mitochondria is
downregulated in the colon of UC patients, suggesting a potential for inefficient sulfite detoxification in the colon.
In this study, I will use patient-derived colon organoids to define how sulfites regulate mitochondrial metabolism
and differentiation in health and in UC (Aim 1), reveal the sulfite-induced and sulfite susceptibility chromatin sites
in the pediatric colon that explains these metabolic and differentiation anomalies (Aim 2), and how sulfites and
the loss of epithelial Mocs1 shape colon biology in the complex gut environment in vivo using physiological
relevant models (Aim 3). This award will advance my training in disease models of IBD, epithelial biology, and
epigenomics as I work toward establishing an innovative career in regenerative nutrition with a focus on pediatric
digestive diseases and continue efforts to enhance diverse representation in the biomedical sciences.
项目摘要
儿童溃疡性结肠炎(UC)的患病率逐年增加。儿科最新证据
UC患者在结肠组织中显示出显著的线粒体损伤。这一点很重要,
线粒体活性是结肠干细胞的庄严功能所必需的,结肠干细胞补充了物理屏障
结肠上皮细胞。由于患者不断暴露于饮食等环境因素,
揭示影响结肠上皮细胞线粒体功能的饮食因素,因为它们对
儿童UC的管理。亚硫酸盐是几种含硫化合物的内源产物,
它们在我们的饮食中也是无处不在的防腐剂。我的结肠类器官的初步数据来自于
儿科患者显示亚硫酸盐对线粒体代谢和分化的有害作用,
儿科UC患者样本的代谢结果。我对206名儿童转录组数据的分析
与UC的研究表明,线粒体中亚硫酸盐下游清除所需的Mocs1基因是
在UC患者的结肠中下调,表明结肠中亚硫酸盐解毒效率低下。
在这项研究中,我将使用患者来源的结肠类器官来定义亚硫酸盐如何调节线粒体代谢。
和分化在健康和UC(目的1),揭示亚硫酸盐诱导和亚硫酸盐敏感性染色质位点
在儿科结肠,解释这些代谢和分化异常(目标2),以及如何亚硫酸盐和
在体内复杂的肠道环境中,使用生理学方法,
相关模型(目标3)。这个奖项将促进我在IBD疾病模型,上皮生物学,
表观基因组学,因为我致力于建立一个创新的职业生涯,在再生营养,重点是儿科
消化系统疾病,并继续努力提高生物医学科学的多样性。
项目成果
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