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: 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
• 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

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。我们假设 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 致病网络延伸至 VEIOBD 之外。我们选择了联盟的主要成员来促进 这些目标，包括三个核心患者招募站点（Scott Snapper 博士，波士顿；Christoph Klein 博士， 慕尼黑； Aleixo Muise 博士（多伦多），每位都拥有免疫表型分析 (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 Sc​​hadt 博士）和数据共享（Larsson Omberg 博士/Sage Bionetwoks）。生成 VEIOBD 蜂窝和 分子图谱，我们的目标是在 VEIOBD 患者中采用多组学方法来生成深入的患者- 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) 来自患者来源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 来自患者血液的转录组学和蛋白质组学。为了进一步了解该数据集，我们将结合这些 深度免疫表型分析数据（通过质谱流式分析）和 VEIOBD 功能表征 源自患者的类器官。在此应用中，我们建议研究 150-200 名 VEIOBD 患者（< 6 岁）和 30- 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 配对外周血样本。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 控制。迄今为止，肠道中导致疾病病理学的多种细胞类型大多是 以总体形式进行研究。为了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 技术。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 VEIOBD 免疫图谱和上皮特征及相关网络。重要的是，我们将分享这些 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。