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Identifying Immune and Epithelial Network Signatures in Very Early Onset Inflammatory Bowel Disease

识别极早发炎症性肠病的免疫和上皮网络特征

基本信息

批准号：
10445069
负责人：
Christoph Klein
金额：
$ 181.58万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10445069
关键词：
6 year old Adolescence Adult Affect Age Atlases Bioinformatics Biological Response Modifiers Biopsy Blood Blood specimen Boston Caregivers Cells Child Childhood Clinical Data Collaborations Collection Communities Complex Coupled Cytometry Data Data Analyses Data Set Defect Development Diagnosis Disease Environmental Health Epithelial Epithelial Cells Family member Frequencies Gastroenterology Generations Genes Genetic Genomics Global Awareness Goals Grant Hematopoietic Stem Cell Transplantation Immune Immune System Diseases Immune system Immunology Inflammatory Bowel Diseases International Intestines Lead Link Microbiology Mission Molecular Mucous Membrane Multiomic Data Mutation Organoids Pathogenesis Pathogenicity Pathology Pathway Analysis Patient Care Patient Recruitments Patients Peer Review Phenotype Physicians Prognostic Marker Proteomics Protocols documentation Publishing Research Research Personnel Sampling Science Scientist Signal Transduction Site Standardization Stromal Cells Systems Biology Technology Testing Tissues Translational Research Variant base causal variant cell type clinically relevant data archive data resource data sharing design diagnostic biomarker disease diagnosis early onset functional genomics genetic disorder diagnosis genetic variant gut microbiome in vitro Model innovation intestinal epithelium member multiple omics new therapeutic target next generation sequencing novel novel therapeutics patient oriented peripheral blood personalized care recruit single-cell RNA sequencing stem cell biology targeted treatment therapeutic target transcriptomics web site

项目摘要

Project Summary Our goal is to build a comprehensive atlas of intestinal epithelial, stromal, and immune cells from both monogenic and polygenic very early onset inflammatory bowel disease (VEOIBD) patients (0<6 years of age) at the single cell level by leveraging the diverse expertise of our VEOIBD Consortium (www.veoibd.org). We hypothesize that developing this atlas will inform upon disease pathogenesis and enable targeted therapeutics for VEOIBD. Moreover, identification and characterization of novel VEOIBD causative genetic variants will inform upon novel IBD pathogenic networks extending beyond VEOIBD. We selected key members of our Consortium to facilitate these goals, including three core patient recruitment sites (Dr. Scott Snapper, Boston; Dr. Christoph Klein, Munich; Dr. Aleixo Muise Toronto), each with combined expertise in immune phenotyping (Snapper), transcriptomics (Dr. Snapper, Dr. Alex Shalek, Dr. Ordovas-Montanes, Kean), proteomics (Dr. Mathias Mann), functional genomics (Drs. Muise, Dr. Klein, Dr. Snapper) as well as expertise in intestinal organoid generation and functional assessments (Dr. Hans Clevers/Dr. Edward Nieuwenhuis), data analysis/network development (Dr. Eric Schadt) and data sharing (Dr. Larsson Omberg/Sage Bionetwoks). To generate a VEOIBD cellular and molecular atlas, our goal is to pursue in VEOIBD patients a multi-omic approach to generate in-depth patient- specific libraries of data including: 1) single cell and bulk transcriptomic and proteomic data generation from biopsies; 2) paired single cell and bulk transcriptomics and proteomics from patient-derived organoids; 3) paired transcriptomics, and proteomics from patient blood. To further inform upon this data set, we will couple these data with deep immune phenotyping (through mass cytometry) and functional characterization of VEOIBD patient-derived organoids. In this application, we propose to study 150-200 VEOIBD patients (< 6 years) and 30- 40 age-matched controls employing bulk and single-cell RNA sequencing and proteomics from biopsies and paired peripheral blood samples. In addition, we will perform deep immune phenotyping on intestinal biopsies (75-100 patients; 15-20 controls) with paired peripheral blood, as well as organoid development coupled with bulk and single cell RNA sequencing and functional assessments on 100-150 VEOIBD patients and 20-30 controls. The multitude of cell types in the intestine contributing to disease pathology has to date been mostly studied in aggregate form. In order to deconvolute the cell specific signal within the tissue and ‘assign’ disease relevance, we will apply our multiscale network (MultiNet) approaches in combination with single cell omics technology. Based on the above data sets, we will validate novel VEOIBD causal gene variants which will not only lead to a better understanding of the disease for these patients but also enhance the development of the VEOIBD immune atlas and epithelial signature and associated networks. Importantly, we will share these libraries of data and organoids with the scientific community to accelerate our mission of identifying therapeutic targets, and cures for VEOIBD.

项目总结