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

• 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
• 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

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.

项目摘要 我们的目标是建立一个完整的肠上皮细胞、基质细胞和免疫细胞图谱， 和多基因极早发性炎症性肠病（VEOIBD）患者（0<6岁）， 通过利用我们的VEOIBD联盟（www.veoibd.org）的多样化专业知识，我们假设 开发该图谱将为疾病发病机制提供信息，并使VEOIBD的靶向治疗成为可能。 此外，新的VEOIBD致病性遗传变体的鉴定和表征将为新的VEOIBD致病性遗传变体的研究提供信息。 IBD致病网络延伸到VEOIBD之外。我们选择了我们联盟的主要成员， 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），每个人都具有免疫表型分析（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 （Hans Clevers博士/Edward Nieuwenhuis博士）、数据分析/网络开发 (Dr. Eric Schadt）和数据共享（Larsson Omberg博士/Sage Bionetwoks）。为了生成VEOIBD细胞和 分子图谱，我们的目标是在VEOIBD患者中寻求一种多组学方法，以产生深入的患者- 具体的数据库包括：1）单细胞和批量转录组学和蛋白质组学数据产生， 活组织检查; 2）来自患者来源的类器官的配对单细胞和批量转录组学和蛋白质组学; 3）配对 转录组学和蛋白质组学。为了进一步了解这一数据集，我们将结合这些 VEOIBD的深度免疫表型分析（通过质谱细胞术）和功能表征数据 患者源性类器官。在本申请中，我们建议研究150-200名VEOIBD患者（< 6岁）和30- 200名VEOIBD患者（< 6岁）。 40个年龄匹配的对照，采用来自活检的批量和单细胞RNA测序和蛋白质组学， 配对的外周血样本。此外，我们将对肠活检进行深层免疫表型分析 （75-100例患者; 15-20例对照），具有配对的外周血，以及类器官发育， 对100-150名VEOIBD患者和20-30名VEOIBD患者进行批量和单细胞RNA测序和功能评估 对照迄今为止，肠道中导致疾病病理学的多种细胞类型主要是 以聚合形式研究。为了去卷积组织内的细胞特异性信号并“分配”疾病 相关性，我们将结合单细胞组学应用我们的多尺度网络（MultiNet）方法 技术.基于上述数据集，我们将验证新的VEOIBD致病基因变体， 这不仅能让这些患者更好地了解疾病，而且还能促进 VE 0 IBD免疫图谱和上皮签名及相关网络。重要的是，我们将分享这些 数据库和类器官与科学界，以加速我们的使命， 目标和治疗方法。