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.

项目总结 儿童溃疡性结肠炎(UC)的患病率呈逐年上升趋势。儿科的最新证据 UC患者结肠组织线粒体明显受损。这一点很重要，因为这是最优的 线粒体活动是结肠干细胞补充物理屏障的庄严功能所必需的 结肠上皮细胞。由于患者经常暴露在饮食等环境因素中，这一点至关重要 揭示影响结肠上皮线粒体功能的饮食因素，因为它们在 儿童UC的管理。亚硫酸盐是几种含硫化合物的内源产物， 它们还作为防腐剂在我们的饮食中无处不在。我的初步数据来自于结肠有机化合物 儿科患者表现出亚硫酸盐对线粒体新陈代谢和分化的有害作用，更糟糕的是 来自儿童UC患者样本的代谢结果。206例儿童转录本数据分析 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 UC患者结肠中亚硫酸盐的表达下调，提示结肠中亚硫酸盐的解毒作用可能无效。 在这项研究中，我将使用患者来源的结肠有机化合物来确定亚硫酸盐如何调节线粒体新陈代谢。 以及在健康和UC中的分化(目标1)，揭示亚硫酸盐诱导的和亚硫酸盐敏感的染色质部位 这解释了这些代谢和分化异常(目标2)，以及亚硫酸盐和 生理学方法研究复杂肠道环境中结肠上皮Mocs1生物学的丢失 相关模型(目标3)。这一奖项将促进我在IBD疾病模型、上皮生物学和 表观基因组学随着我致力于建立再生营养领域的创新职业生涯，专注于儿科 我们还将继续努力加强生物医学科学领域的多样性代表性。