Durability of Epithelial Defects in Crohn's Disease Intestine

克罗恩病肠道上皮缺陷的持久性

基本信息

批准号：
10322741
负责人：
Kelli Lynn VanDussen
金额：
$ 11.93万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322741
关键词：
Address Adult Aftercare Area Behavior Biological Biopsy Cell Line Cell physiology Childhood Chronic Clinical Complement Crohn&apos s disease Data Defect Digestive System Disorders Disease Disease Outcome Disease Progression Endoscopy Enterocytes Environment Environmental Exposure Enzymes Epithelial Epithelial Cells Exhibits Functional disorder Funding Gene Cluster Goals Histologic Host Defense Human Ileal Diseases Immune response In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-12 Intestinal Diseases Intestines Knowledge Length Location Mendelian disorder Microvillus inclusion disease Modeling Molecular Monoclonal Antibodies Mucous Membrane Operative Surgical Procedures Pathogenesis Patients Pediatric Crohn&apos s disease Phase III Clinical Trials Phenotype Prognosis Progressive Disease Proteins Refractory Reporting Research Personnel Sampling Secondary to Surface TNF gene Testing Tissue Sample Tissues absorption apical membrane biobank cellular microvillus chronic inflammatory disease clinically relevant cohort disease prognosis disorder control dysbiosis early onset experience gastrointestinal genetic signature healing improved in vivo indexing insight interleukin-23 intestinal epithelium intestinal homeostasis lipid metabolism microbial microbial host microbiome microbiome alteration negative affect novel patient subsets personalized therapeutic phenotypic data prognostic prognostic model protein expression response restoration targeted treatment therapeutic target

项目摘要

PROJECT SUMMARY/ABSTRACT Crohn’s disease is a debilitating and progressive inflammatory disease of the gastrointestinal tract. Defects in epithelial cells are thought to contribute to Crohn’s disease progression. However, the biological drivers and mechanisms of epithelial defects are not well understood. If epithelial cell defects occur secondary to the inflammatory and altered microbiome exposures present in the patient, treatments targeting these exposures would be predicted to resolve the epithelial defects. Alternatively, if epithelial defects are primary or durable contributors to Crohn’s disease progression, they would be predicted to persist despite treatment, as no current treatments target the epithelium. This project aims to distinguish these two models in order to improve Crohn’s disease prognosis. We have identified two quantitative epithelial defects related to microvillar dysfunction in Crohn’s disease ileal tissues lacking histological inflammation, suggesting that microvillar defects could be durable contributors to Crohn’s disease progression. Microvilli are apical membrane protrusions on epithelial cells that increase surface area for absorption and provide a physical location for the enrichment of enzymes, transporters, and host defense proteins critical for intestinal homeostasis. Loss of microvilli or certain microvillar localized proteins is associated with microvillus inclusion disease, very-early onset inflammatory bowel disease, and enteropathy. For this project, we propose to track the quantitative microvillar defects in vivo (pre- and post- treatment) and in vitro (epithelium removed from inflammatory/microbial exposures). We have developed an overarching hypothesis that epithelial microvillar defects will be durable in a Crohn’s disease patient subset with a more aggressive disease course. In Aim 1, we will investigate the durability of the microvillar defects in vivo using existing longitudinal samples and data from the pediatric RISK Crohn’s disease cohort and control subjects. We predict that the microvillar defects are more likely to persist in patients with progressive disease behavior, lack of anti-TNF response, and requirement for surgery. We will also perform association analysis with the microvillar defect phenotypes, clinical parameters, and microbiome profiles to identify ways we can potentially improve patient subsetting. In Aim 2, we will investigate the durability of the microvillar defects in vitro using human intestinal epithelial spheroid lines derived from Crohn’s disease and control patient biopsy tissues. Our preliminary analysis indicates that the microvillar defects will be durable in a subset of spheroid lines. We will test if durable spheroid microvillar defects are associated with decreased lipid metabolism, a critical enterocyte function predicted to be decreased by our preliminary analysis. Overall, this project will determine whether microvillar defects are durable epithelial contributors to Crohn’s disease progression. In addition, it will begin to identify the Crohn’s disease patient subset that would be most likely to benefit from a personalized therapeutic approach to restore epithelial cell function.

项目摘要/摘要克罗恩病是胃肠道的一种令人衰弱和进行性炎症性疾病。缺陷上皮细胞被认为有助于克罗恩病的进展。但是，生物驱动器和上皮缺陷的机制尚不清楚。如果上皮细胞缺陷发生于继发于患者中存在的炎症和改变的微生物组暴露，针对这些暴露的治疗预计将解决上皮缺陷。克罗恩病进展的贡献者，预计他们将持续目的地治疗，因为没有当前治疗靶向上皮。该项目旨在区分这两种模型，以改善克罗恩疾病预后。我们已经确定了与微伏特功能障碍有关的两个定量上皮缺陷克罗恩病的回肠组织缺乏组织学炎症，这表明微绒毛缺陷可能是克罗恩病进展的持久贡献者。微绒毛是上皮上的根尖膜突起增加滥用表面积并为富集酶提供物理位置的细胞，转运蛋白和宿主防御蛋白对肠内稳态至关重要。微绒毛或某些微绒毛的损失局部蛋白质与微绒毛膜疾病有关，很早发作炎症性肠病，和肠病。对于这个项目，我们建议在体内跟踪定量微伏缺陷（前后治疗）和体外（从炎症/微生物暴露中除去上皮）。我们已经开发了总体假设是，在克罗恩病患者子群中，上皮微绒毛缺陷将是持久的更具侵略性的疾病病程。在AIM 1中，我们将研究体内微伏缺陷的耐用性使用现有的纵向样本和来自儿科风险克罗恩病队列和控制的数据主题。我们预测，在进行性疾病的患者中，微绒毛缺陷更有可能持续行为，缺乏抗TNF反应以及对手术的要求。我们还将与微伏缺陷表型，临床参数和微生物组轮廓，以识别我们可以潜在的方法改善患者子集。在AIM 2中，我们将在体外研究微绒毛缺陷的耐用性人肠上皮球形线系源自克罗恩病并控制患者活检组织。我们的初步分析表明，在球形线的子集中，微伏缺陷将是耐用的。我们将测试是否耐用球形微型旋转缺陷与改善的脂质代谢相关，这是关键的肠op 通过我们的初步分析可以改善功能。总体而言，该项目将确定是否微绒毛缺陷是克罗恩病进展的耐用上皮贡献者。另外，它将开始确定最有可能从个性化疗法中受益的克罗恩病患者子集恢复上皮细胞功能的方法。