Intestinal Stem Cell Metabolism in Inflammatory Bowel Disease Mucosal Healing

炎症性肠病粘膜愈合中的肠道干细胞代谢

• 批准号: 10606371
• 负责人: Heather Mentrup
• 金额: $ 8.31万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-10 至 2026-08-09
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606371
• 关键词: 3-Dimensional; Atrophic; Bioenergetics; Biological Models; Bone Marrow; Cell Proliferation; Cells; Cellular Metabolic Process; Chronic; Colitis; Complex; Coupled; Crohn' s disease; Deoxyglucose; Development; Disease; Disease remission; Energy Supply; Environment; Epithelial Cells; Epithelium; Exposure to; Financial Hardship; Frequencies; Genus Hippocampus; Glucose; Glucose Transporter; Glycolysis; Glycolysis Inhibition; Goals; Grant; Health; Histologic; Homeostasis; Human; Immune; Immune response; Immunotherapy; Impairment; Individual; Inflammation; Inflammatory Bowel Diseases; Injury; Intestines; LGR5 gene; Macrophage; Mass Spectrum Analysis; Messenger RNA; Metabolic; Metabolism; Modeling; Molecular; Morbidity - disease rate; Morphology; Mucous Membrane; Mus; Natural regeneration; Organoids; Output; Patients; Pediatric Hospitals; Pharmaceutical Preparations; Phenotype; Play; Population; Process; Production; Proliferating; Radiation; Recovery; Recurrence; Regenerative response; Relapse; Reporter; Research; Research Personnel; Resolution; Resources; Role; SLC2A1 gene; Societies; Sodium Dextran Sulfate; Structure; Surface; System; Tamoxifen; Therapeutic Intervention; Tissues; Training; Ulcerative Colitis; United States; Universities; Up-Regulation; Work; biomarker discovery; biomarker identification; cohort; cost; design; epithelial injury; epithelial repair; epithelium regeneration; experience; fetal; glucose transport; healing; immunomodulatory therapies; immunoregulation; improved; injury and repair; intestinal epithelium; intestinal injury; metabolic profile; metabolome; metabolomics; molecular phenotype; novel; novel marker; novel therapeutic intervention; novel therapeutics; regenerative; relapse patients; repair function; repair model; repaired; reparative capacity; response; self-renewal; stem cell biomarkers; stem cell function; stem cell population; stem cells; stem-like cell; success; targeted treatment; tissue repair; treatment strategy

Project Summary/Abstract Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, is a complex disease that results in long-term inflammation within the intestine. Approximately 3.1 million individuals in the United States are currently living with IBD with 70,000 newly identified cases each year. This presents a significant financial burden on individuals and the economy, costing over $14.6 billion annually in the United States. Patients with IBD experience cycles of inflammation and tissue damage followed by periods of repair and remission. The majority of immunotherapies for IBD treatment have been focused on modifying the immune response, which are highly effective, but nearly a third of patients relapse within 12 months. Redirecting our focus on how the mucosa is repaired will likely provide an added benefit in IBD treatment when coupled with immune modulating therapies. The unique ability of intestinal stem cells (ISCs) to self-renew and differentiate into functional epithelial cells makes them an indispensable component of tissue repair. In the gut, different populations of damage-associated ISCs exist, including a ISC population that emerges during colitis-associated inflammation. To better understand this population, we developed a 3-D murine organoid model system that enriches for these cells. This system will be utilized to study how cell metabolism impacts the reparative function of colitis-associated ISCs. The use of metabolite analysis via mass spectrometry and metabolic bioenergetic analysis using a Seahorse XFe96 Analyzer will allow us to generate a metabolic profile for these cells. We are also developing a novel mouse reporter line to study how glucose transporters impact the reparative function of colitis-associated ISCs in an intestinal injury-repair model of inflammation. Successful completion of this grant will allow us to better understand how the cell metabolism of colitis-associated ISCs impacts mucosal healing. Our long-term goal is to identify biomarkers of colitis- associated ISCs to define mucosal healing and disease remission more accurately. A better understanding of the molecular processes that influence colitis-associated ISC function will encourage the development of novel therapeutics that help to regenerate the damaged epithelium. This work is being conducted at the Rangos Research Center of UPMC Children’s Hospital of Pittsburgh and the University of Pittsburgh, which is an outstanding research environment that provides the trainee with the physical resources, research cohorts, and intellectual resources to successful complete this work. The detailed training plan designed will help develop the trainee’s scientific expertise in ISC metabolism, biomarker discovery, and IBD, and facilitate the transition into an independent investigator in IBD research.

项目摘要/摘要 炎症性肠病（IBD），包括溃疡性结肠炎和克罗恩病，是一种复杂的疾病 这导致肠内长期炎症。曼联大约有310万个人 各州目前每年都有70,000个新识别案件的IBD。这是一个重要的 美国和经济的财务燃烧，每年在美国耗资超过146亿美元。 IBD患者经历感染和组织损伤的周期，然后是修复期和 缓解。 IBD治疗的大多数免疫疗法都集中在修改免疫 重定向我们的反应，这是非常有效的，但几乎三分之一的患者在12个月内接纳。 关注粘膜修复的方式可能会在IBD治疗中提供额外的好处 免疫调节疗法。肠干细胞（ISC）自我更新和 分化为功能性上皮细胞使其成为组织修复必不可少的组成部分。在 肠道，存在不同损害相关的ISC种群，包括在 结肠炎相关的炎症。为了更好地了解这一人群，我们开发了一个3-D鼠类器官 富含这些细胞的模型系统。该系统将用于研究细胞代谢如何影响 结肠炎相关的ISC的修复功能。通过质谱法和代谢物分析的使用 使用Seahorse XFE96分析仪的代谢生物能分析将使我们能够产生代谢 这些细胞的轮廓。我们还正在开发一条新型的小鼠记者系，以研究葡萄糖 转运蛋白在肠道损伤修复模型中影响与结肠炎相关的ISC的修复功能 炎。成功完成这笔赠款将使我们能够更好地了解细胞代谢 结肠炎相关的ISC会影响粘膜愈合。我们的长期目标是确定结肠炎的生物标志物 相关的ISC更准确地定义粘膜愈合和疾病缓解。更好的理解 影响结肠炎相关的ISC功能的分子过程将鼓励发展 新的理论，有助于再生受损的上皮。这项工作正在 匹兹堡UPMC儿童医院和匹兹堡大学的Rangos研究中心， 是一个杰出的研究环境，可为学员提供物理资源，研究 共同完成这项工作的人群和智力资源。设计的详细培训计划将 帮助发展学员在ISC代谢，生物标志物发现和IBD方面的科学专业知识，以及 促进过渡到IBD研究中的独立研究者。