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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要/摘要炎症性肠病（IBD），包括溃疡性结肠炎和克罗恩病，是一种复杂的疾病导致美国大约 310 万人肠道内出现长期炎症。目前，各州每年新发现 70,000 例 IBD 病例，这是一个重大数字。给个人和经济造成的财务负担，在美国每年造成超过 146 亿美元的损失。 IBD 患者会经历炎症和组织损伤的循环，然后是修复和组织损伤的时期。大多数 IBD 免疫疗法都集中于改变免疫系统。反应非常有效，但近三分之一的患者在 12 个月内复发。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。肠道干细胞（ISC）具有自我更新和自我更新的独特能力。分化为功能性上皮细胞使其成为组织修复中不可或缺的组成部分。肠道中存在不同的损伤相关 ISC 群体，包括在为了更好地了解这一群体，我们开发了 3D 小鼠类器官。丰富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 ISC 的修复功能通过质谱法进行代谢物分析。使用 Seahorse XFe96 分析仪进行代谢生物能分析将使我们能够生成代谢我们还在开发一种新型小鼠报告系来研究葡萄糖如何变化。转运蛋白影响肠道损伤修复模型中结肠炎相关 ISC 的修复功能成功完成这项资助将使我们更好地了解细胞代谢是如何进行的。结肠炎相关 ISC 的数量影响粘膜愈合，我们的长期目标是确定结肠炎的生物标志物。相关 ISC 可以更准确地定义粘膜愈合和疾病缓解。影响结肠炎相关 ISC 功能的分子过程将促进有助于再生受损上皮的新疗法正在进行这项工作。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，为学员提供物质资源、研究成功完成这项工作的队列和智力资源设计的详细培训计划将。帮助学员培养 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 IBD 研究独立研究者的转变。