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：
10056563
负责人：
Christoph Klein
金额：
$ 190.65万
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/10056563
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 Epithelium 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 immunoregulation 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.

项目概要我们的目标是建立一个来自单基因的肠上皮细胞、基质细胞和免疫细胞的综合图谱。和多基因极早发炎症性肠病 (VEOIBD) 患者（0<6 岁）通过利用我们 VEIOBD 联盟 (www.veoibd.org) 的多样化专业知识，在细胞水平上实现。开发该图谱将了解疾病发病机制并实现 VEIOBD 的靶向治疗。此外，新的 VEIOBD 致病基因变异的鉴定和表征将为新的 VEIOBD 致病基因变异提供信息。 IBD 致病网络延伸到 VEIOBD 之外。我们选择了联盟的主要成员来促进发展。这些目标，包括三个核心患者招募地点（Scott Snapper 博士，波士顿；Christoph Klein 博士，慕尼黑；Aleixo Muise 博士 (多伦多)，两人均拥有免疫表型分析 (Snapper) 方面的综合专业知识，转录组学（Snapper 博士、Alex Shalek 博士、Ordovas-Montanes 博士、Kean）、蛋白质组学（Mathias Mann 博士）、功能基因组学（Muise 博士、Klein 博士、Snapper 博士）以及肠道类器官生成方面的专业知识和功能评估（Hans Clevers 博士/Edward Nieuwenhuis 博士）、数据分析/网络开发（Eric Schadt 博士）和数据共享（Larsson Omberg 博士/Sage Bionetwoks）生成 VEIOBD 细胞和数据。分子图谱，我们的目标是在 VEIOBD 患者中追求多组学方法，以生成深入的患者- 具体的数据库包括：1）单细胞和批量转录组和蛋白质组数据生成活检；2) 配对单细胞和来自患者的类器官的批量转录组学和蛋白质组学；3) 配对为了进一步了解该数据集，我们将结合这些数据。深度免疫表型分析数据（通过质谱流式分析）和 VEIOBD 功能表征在此应用中，我们建议研究 150-200 名 VEIOBD 患者（< 6 岁）和 30-30 名患者。 40 个年龄匹配的对照，采用来自活检和活检的大量单细胞 RNA 测序和蛋白质组学此外，我们将对肠道活检进行深度免疫表型分析。（75-100 名患者；15-20 名对照）配对外周血，以及类器官发育对 100-150 名 VEIOBD 患者和 20-30 名患者进行批量和单细胞 RNA 测序和功能评估迄今为止，肠道中的多种细胞类型对疾病病理学有贡献。以聚合形式进行研究，以解卷积组织内的细胞特异性信号并“分配”疾病。相关性，我们将应用我们的多尺度网络（MultiNet）方法与单细胞组学相结合基于上述数据集，我们将验证新的 VEIOBD 致病基因变异，该变异不会不仅可以让这些患者更好地了解疾病，还可以促进疾病的发展重要的是，我们将分享这些 VEIOBD 免疫图谱和上皮特征以及相关网络。与科学界合作的数据和类器官库，以加速我们确定治疗方法的使命 VEIOBD 的目标和治疗方法。