Intestinal Stem Cell Metabolism in Inflammatory Bowel Disease Mucosal Healing

项目总结/摘要 炎症性肠病（Inflammatory Bowel Disease，IBD）包括溃疡性结肠炎和克罗恩病，是一种复杂的疾病 导致肠道长期发炎美国约有310万人 各州目前患有IBD，每年新发现70，000例病例。这是一个重要的 对个人和经济的财政负担，在美国每年花费超过146亿美元。 患有IBD的患者经历炎症和组织损伤的周期，随后是修复期， 缓解。IBD治疗的大多数免疫疗法都集中在修饰免疫原性。 这些药物非常有效，但近三分之一的患者在12个月内复发。重定向我们的 关注粘膜如何修复可能会在IBD治疗中提供额外的益处， 免疫调节疗法。肠干细胞（ISCs）自我更新和再生的独特能力， 分化成功能性上皮细胞使它们成为组织修复不可或缺的组成部分。在 在肠道中，存在不同的损伤相关ISC群体，包括在肠道中出现的ISC群体。 结肠炎相关炎症。为了更好地了解这一群体，我们开发了一个三维小鼠类器官， 为这些细胞富集的模型系统。该系统将用于研究细胞代谢如何影响 结肠炎相关ISCs的修复功能。通过质谱法进行代谢物分析的应用， 使用Seahorse XFe 96分析仪进行代谢生物能分析将使我们能够生成代谢生物能分析。 这些细胞的特征我们还在开发一种新的小鼠报告细胞系，以研究葡萄糖 转运蛋白影响结肠炎相关ISCs的修复功能， 炎症这项资助的成功完成将使我们更好地了解细胞代谢是如何 结肠炎相关的ISCs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，以更准确地定义粘膜愈合和疾病缓解。更好地理解 影响结肠炎相关ISC功能的分子过程将促进 帮助受损上皮再生的新疗法。这项工作正在进行， 匹兹堡UPMC儿童医院和匹兹堡大学的Rangos研究中心， 是一个优秀的研究环境，为学员提供物理资源，研究 团队和智力资源来成功完成这项工作。设计的详细培训计划将 帮助培养受训者在ISC代谢、生物标志物发现和IBD方面的科学专业知识，以及 促进转变为IBD研究的独立研究者。

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.