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: 10263246
• 负责人: Christoph Klein
• 金额: $ 181.23万
• 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/10263246
• 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.

项目摘要 我们的目标是建立一个由两种单基因的肠上皮，基质和免疫小球的全面地图集 和多基因的早期发作炎症性肠病（VEOIBD）患者（0 <6岁） 通过利用我们的Veoibd财团（www.veoibd.org）的潜水专业知识来利用细胞水平。我们假设这一点 开发此地图集将为疾病发病机理提供信息，并为VEOIBD实现靶向疗法。 此外，新型VEOIBD致病遗传变异的识别和表征将告知新颖 IBD致病网络延伸到Veoibd之外。我们选择了我们财团的主要成员来促进 这些目标，包括三个核心的患者招聘网站（波士顿的斯科特·斯纳普（Scott Snapper）；克里斯托夫·克莱因（Christoph Klein）博士 慕尼黑; Aleixo Muise Toronto博士），每个人都具有免疫表型（Snapper）的联合专业知识， 转录组学（Snapper博士，Alex Shalek博士，Kean Ordovas-Montanes博士），蛋白质组学（Mathias Mann博士）， 功能基因组学（Muise Dr.Muise，Klein博士，Snapper博士）以及肠道器官的专业知识 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/Sage Bionetwoks博士）。生成一个veoibd细胞和 分子地图集，我们的目标是在VEOIBD患者中追求一种多摩变方法，以产生深入的患者 - 数据的特定库，包括：1）从 活检； 2）与患者衍生的类器官配对的单细胞和大量转录组和蛋白质组学； 3）配对 转录组学和患者血液中的蛋白质组学。为了进一步告知此数据集，我们将策划这些 具有深度免疫表型的数据（通过质量细胞仪）和VEOIBD的功能表征 患者衍生的类器官。在此应用中，我们建议研究150-200名VEOIBD患者（<6年）和30-- 40个年龄匹配的对照，采用活检和单细胞RNA测序和蛋白质组学和蛋白质组学的对照组 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 （75-100名患者； 15-20个对照组），配对的外周血以及类器官发育与 对100-150名VEOIBD患者和20-30的批量和单细胞RNA测序和功能评估 控件。迄今为止，导致疾病病理学的肠道类型的多种细胞类型主要是 研究以骨料形式进行。为了在组织中反驳细胞特异性信号和“分配”疾病 相关性，我们将使用我们的多尺度网络（多字）方法与单个单元格组合使用 技术。基于上述数据集，我们将验证新型的VEOIBD因果基因变种 仅导致对这些患者的疾病有更好的了解，但也增强了 VEOIBD免疫地图集和上皮签名和相关网络。重要的是，我们将分享这些 与科学界的数据和器官库，以加速我们识别治疗的使命 目标和治疗方法。