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.

项目概要/摘要克罗恩病是一种使人衰弱的进行性胃肠道炎症性疾病。上皮细胞被认为有助于克罗恩病的进展，然而，其生物学驱动因素和上皮细胞缺陷的机制尚不清楚。患者体内存在炎症和改变的微生物组暴露，针对这些暴露的治疗或者，如果上皮缺陷是原发性或持久性的，则预计可以解决上皮缺陷。克罗恩病进展的贡献者，预计尽管接受治疗，它们仍将持续存在，因为目前没有该项目旨在区分这两种模型，以改善克罗恩病。我们已经确定了与微绒毛功能障碍相关的两种定量上皮缺陷。克罗恩病回肠组织缺乏组织学炎症，表明微绒毛缺陷可能与克罗恩病进展的持久因素是上皮细胞顶膜突起。细胞增加吸收表面积并为酶的富集提供物理位置，转运蛋白和对肠道稳态至关重要的宿主防御蛋白。局部蛋白与微绒毛包涵体病、极早发性炎症性肠病、对于这个项目，我们建议跟踪体内的定量微绒毛缺陷（治疗前和治疗后）。治疗）和体外（从炎症/微生物暴露中去除上皮）。总体假设是，上皮微绒毛缺陷在克罗恩病患者亚群中将持续存在在目标 1 中，我们将研究体内微绒毛缺陷的持久性。使用儿科风险克罗恩病队列和对照的现有纵向样本和数据我们预测，微绒毛缺陷更有可能在疾病进展的患者中持续存在。我们还将进行关联分析。微绒毛缺陷表型、临床参数和微生物组概况，以确定我们可以潜在的方法在目标 2 中，我们将使用体外方法研究微绒毛缺陷的持久性。源自克罗恩病的人肠上皮球体系和对照患者活检组织。初步分析表明，微绒毛缺陷将在球状体线的子集中持久存在。测试持久的球状微绒毛缺陷是否与脂质代谢下降有关，脂质代谢是一种关键的肠上皮细胞总体而言，我们初步分析预计该项目将减少功能。微绒毛缺陷是克罗恩病进展的持久上皮因素。确定最有可能从个性化治疗中受益的克罗恩病患者子集恢复上皮细胞功能的方法。