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

• 批准号: 10722914
• 负责人: Babajide Ojo
• 金额: $ 9.15万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10722914
• 关键词: Adverse effects; Affect; American; Animal Model; Award; Bar Codes; Biology; Biopsy; Cell Differentiation process; Cell Respiration; Cells; Cellular Metabolic Process; Child; Child Nutrition; Childhood; Chromatin; Colitis; Colon; Colonic inflammation; Complex; Consumption; Data; Defect; Developed Countries; Diet; Dietary Factors; Digestive System Disorders; Disease; Disease Management; Disease model; Drug Metabolic Detoxication; Environment; Environmental Risk Factor; Epithelium; Excision; Exposure to; Food Preservatives; Foundations; Funding; Future; Genes; Goals; Health; Homeostasis; Human; Impairment; Incidence; Inflammatory Bowel Diseases; Ingestion; Intake; Intestines; Maintenance; Metabolic; Metabolism; Mitochondria; Mitochondrial DNA; Modeling; Mus; Mutation; Natural regeneration; Organoids; Outcome; Pathway interactions; Patients; Pediatric ulcerative colitis; Phase; Phenotype; Physiological; Play; Predisposition; Prevalence; Publishing; Recovery; Research; Research Personnel; Role; Safety; Sampling; Science; Shapes; Signal Transduction; Site; Source; Sulfites; Sulfur; Tissues; Training; Ulcerative Colitis; United States National Institutes of Health; Variant; Work; biobank; career; dietary; disorder control; epigenome; epigenomics; epithelial injury; epithelial repair; epithelial stem cell; feeding; gastrointestinal epithelium; gut microbiota; human tissue; in vivo; inhibitor; innovation; intestinal barrier; intestinal epithelium; mitochondrial DNA mutation; mitochondrial dysfunction; mitochondrial metabolism; molybdenum cofactor; mouse model; nutrition; pediatric patients; programs; regenerative; response; self-renewal; skills; stem cell derived tissues; stem cell differentiation; stem cells; transcriptomics; western diet

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.

项目概要 儿童溃疡性结肠炎（UC）的患病率逐年增加。儿科的最新证据 UC患者在结肠组织中表现出明显的线粒体损伤。这很重要，因为它是最佳的 线粒体活性是结肠干细胞补充物理屏障的重要功能所必需的 结肠上皮。由于患者不断暴露于饮食等环境因素，因此至关重要 揭示影响结肠上皮线粒体功能的饮食因素，因为它们对于 儿童 UC 的管理。亚硫酸盐是几种含硫化合物的内源产物， 它们作为防腐剂在我们的饮食中也无处不在。我的结肠类器官初步数据来自 儿科患者表现出亚硫酸盐对线粒体代谢和分化有不利作用，情况更糟 儿科 UC 患者样本的代谢结果。我对 206 名儿童的转录组数据的分析 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的效率可能较低。 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 以及健康和 UC 中的分化（目标 1），揭示亚硫酸盐诱导的染色质位点和亚硫酸盐易感性染色质位点 在儿科结肠中解释这些代谢和分化异常（目标 2），以及亚硫酸盐和 使用生理学方法在体内复杂的肠道环境中上皮 Mocs1 形状结肠生物学的丧失 相关模型（目标 3）。该奖项将促进我在 IBD 疾病模型、上皮生物学和 表观基因组学，我致力于在再生营养领域建立创新的职业生涯，重点关注儿科 消化系统疾病，并继续努力增强生物医学科学的多元化代表性。