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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：
10436845
负责人：
Rachel Levantovsky
金额：
$ 4.52万
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/10436845
关键词：
Adopted Affect African African ancestry Agonist Air Area Biological Assay Biopsy Cell physiology Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Clinical Clinical Research Colectomy Colon Complement Complication Crohn&apos s disease Data Data Set Development Dinoprostone Disease Electrical Resistance Environment Epithelial Epithelial Cells Epitopes Etiology European 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 Immune Immunofluorescence Immunologic In Vitro Inflammation Inflammatory Interleukin-17 Intervention Intestines Lipids Liquid substance Maintenance Measures Mediating Mediator of activation protein Mesenchymal Modeling Morbidity - disease rate Mucous Membrane Organoids Outcome Pathogenesis Pathologic Pathology Pathway interactions Patient-Focused Outcomes Patients Pattern Phenotype Physiological Play Polymerase Chain Reaction Population Proteins RNA 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 base behavior influence chronic inflammatory disease clinical care cohort cytokine data acquisition epithelial injury genetic variant genome wide association study genome-wide 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.

项目总结