Defining mechanisms of perianal fistula inception in African and European ancestry Crohn's disease patients

非洲和欧洲克罗恩病患者肛周瘘起始的定义机制

基本信息

批准号：
10649458
负责人：
Rachel Levantovsky
金额：
$ 5.27万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
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：
2021-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649458
关键词：
Adopted Affect African ancestry Agonist Air Anal Fistula Anus Area Biological Assay Biopsy Cell physiology Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Clinical Clinical Research Cohort Studies Colectomy Collaborations Colorectal Complement Complication Crohn&apos s disease Data Data Set Development Dinoprostone Disease Disparate Electrical Resistance Environment Epithelial Cells Epithelium Epitopes Etiology European ancestry Event Excision Fellowship Fibrosis Fistula Fostering Functional disorder Gastrointestinal tract structure Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Genetic Risk Genetic Transcription Genomics Genotype Goals Health Home IL17 gene Immune Immunofluorescence Immunologic In Vitro Inflammation Inflammatory Intervention Intestines Lipids Liquid substance Maintenance Measures Mediating Mediator Mesenchymal Modeling Morbidity - disease rate Mucous Membrane Organoids Outcome Pathogenesis Pathologic Pathology Pathway interactions Patient-Focused Outcomes Patients Pattern Penetration Phenotype Physiological Play Polymerase Chain Reaction Population Predisposition Proteins RNA Receptor Inhibition Recording of previous events Rectum Risk Role Sampling Signal Pathway Signal Transduction Specimen Stains Stimulus Stromal Cells System TNF gene Tight Junctions Time Tissue-Specific Gene Expression Tissues Training Translations Variant Visualization WFDC2 gene Work ancestry analysis behavior influence chronic inflammatory disease clinical care cohort cytokine data acquisition epithelial injury genetic variant genome wide association study genome-wide genome-wide analysis healing improved in vivo indexing insight interleukin-17C intestinal epithelium loss of function monolayer novel patient population power analysis protein expression receptor recruit rectal risk variant single cell sequencing single-cell RNA sequencing transcriptome transcriptome sequencing treatment response validation studies wound wound healing

项目摘要

PROJECT SUMMARY Crohn’s disease (CD) is characterized by progressive, transmural inflammation that can affect any region of the gastrointestinal tract. Penetrating complications, most often perianal fistulae, will affect up to 50% of CD patients over their disease course. Perianal fistulae are a high morbidity CD complication with poor treatment response. African ancestry (AA) patients have higher rates of perianal disease, including perianal fistula, than European ancestry (EA) CD patients. Many of the genetic advances of the genome wide association era are from studies wherein AA patients are underrepresented. PTGER4 is the only risk locus with strong association signals in AA populations. There is a need to include AA patients in genetic and genomic studies of CD, particularly in the context of perianal fistula, to better understand drivers of disease and improve clinical outcomes. Aim 1 seeks to construct a single cell genomics cohort of AA and EA patients with a history of perianal fistulizing CD. To date, there is no single cell sequencing dataset of CD samples with a focus on the rectum or fistula, nor a dataset comparing single cell gene expression between these ancestry groups in CD. We will perform CITE- sequencing on resection tissues from proctectomies and colectomies in patients with severe CD and history of perianal fistula. We will also collect rectal biopsies from areas of active inflammation and from un-involved rectum or colon for single cell RNA sequencing. From these data, we will identify differential gene expression modules that will be validated by projection onto available bulk RNA sequencing data from larger CD patient cohorts. Single cell capture of both RNA and protein expression will provide unprecedented granularity into cell populations important in fistula progression and illuminate any differences between patient populations. In Aim 2, we will further explore drivers of fistula pathogenesis. We identify IL-17 and PGE2 signaling as candidate pathways that influence epithelial integrity in the context of inflammation and epithelial-mesenchymal transition (EMT), promoting fistula inception. We will culture epithelial monolayers long-term from patient-derived organoids to model epithelial differentiation, barrier function, and EMT. We will use this system to assess the effects of PGE2 and IL-17 receptor agonism and inhibition on epithelial cells, and how this may influence wound healing and mediate fistula inception. In this way, we will be able to interrogate specific signaling pathways and their contributions to epithelial health using functional readouts. The academic environment at Mount Sinai is unparalleled to perform this work. Mount Sinai is home to pioneers in IBD clinical care and research, who collaborate in meaningful ways while working with one of the most diverse patient populations in the world. The training plan for this fellowship takes full advantage. Together, the studies described herein will provide important insight into perianal fistula inception and which gene modules might make a patient susceptible. This proposal combines direct ex vivo single cell genomics with in vitro functional studies for a robust inquiry into a high morbidity complication that affects diverse patient populations.

项目摘要克罗恩氏病（CD）的特征是进行性透壁炎症，可能影响您的任何区域胃肠道的穿透性汇编，最常见的瘘管会影响多达50％的CD患者在疾病的病程中。非洲血统（AA）患者的毛过疾病率很高，含有perianal瘘，而不是欧洲祖先（EA）CD患者。其中AA患者的表现不足。种群。 perian瘘的背景，以更好地了解疾病的驱动因素并改善临床结果。 AIM 1试图构建AA的单个细胞基因组学组和具有Perianal Fistuling病史的食品 CD。比较CD中这些祖先的单个Celle表达的数据集。严重CD患者的患者中的凝乳切除术和结肠切除术的分析和病史我们还将从主动炎症区域收集直肠活检和直肠从这些数据中进行单细胞RNA测序的结肠。这将通过投影对来自较大较大CD患者队列的可用大量RNA测序数据进行验证。 RNA和蛋白质表达的单细胞捕获将为细胞提供前所未有的粒度人群在瘘管进度和照明中很重要，种群之间的任何差异。在AIM 2中，我们将进一步探索瘘管发病机理的驱动因素。在炎症和上皮膜中影响上皮完整性的候选途径过渡（EMT），促进瘘管的成立。有机体以模拟上皮差异，屏障功能和EMT。 PGE2和IL-17受体激动剂和不可自然性对上皮细胞的影响，以及如何影响伤口治愈和介导瘘管，以这种方式，我们将能够询问特定的信号通路他们使用功能读数对上皮健康的贡献。西奈山的学术环境无法执行这项工作。在IBD临床护理和研究中，他们在与最多样化之一的同时以有意义的方式合作研究金的培训计划充分利用了研究本文描述的将提供重要的成分，以及哪些基因模块可能会产生患者易感性。为了对高病态压缩进行强有力的调查，以使患者种群多样化。