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: 10670325
• 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/10670325
• 关键词: 6 year old; Acceleration; Adolescence; Adult; Affect; Age; Atlases; Bioinformatics; Biological Response Modifiers; Biopsy; Blood; Blood specimen; Boston; Caregivers; Cells; Child; Childhood; Classification; Clinical Data; Collaborations; Collection; Communities; Complex; Coupled; Cytometry; Data; Data Analyses; Data Set; Defect; Development; Diagnosis; Disease; Environment; Environmental Health; 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; Patient Care; Patient Recruitments; Patients; Peer Review; Phenotype; Physicians; Prognostic Marker; Proteomics; Protocols documentation; Publishing; Research; Research Personnel; Resources; Sampling; Science; Scientist; Signal Transduction; Site; Standardization; Stromal Cells; Systems Biology; Technology; Testing; Tissues; Translational Research; Variant; causal variant; cell type; clinically relevant; data library; 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全面的图谱，包括肠上皮细胞、基质细胞和免疫细胞 和多基因极早发性炎症性肠病(VEOIBD)患者(0&lt；6岁)在单一 通过利用我们的VEOIBD联盟(www.veoibd.org)的不同专业知识，在细胞级别进行测试。我们假设 开发这一图谱将为疾病的发病机制提供信息，并使VEOIBD的靶向治疗成为可能。 此外，新的VEOIBD致病基因变异的鉴定和特征将为新的 IBD的致病网络延伸到VEOIBD之外。我们选择了我们联盟的主要成员来促进 这些目标包括三个核心患者招募网站(波士顿的Scott Snapper博士、Christoph Klein博士、 慕尼黑；多伦多Aleixo Muise博士)，每个人都拥有免疫表型鉴定方面的综合专业知识(Snapper)， 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)以及在肠道类有机物质生成方面的专业知识 和功能评估(汉斯·克利弗斯博士/爱德华·纽文赫伊斯博士)、数据分析/网络发展 (Eric Schadt博士)和数据共享(Larsson Omberg/Sage Bionetwoks博士)。以产生VEOIBD细胞和 分子图谱，我们的目标是在VEOIBD患者中追求一种多组学方法来产生深入的患者- 特定的数据库包括：1)单细胞和批量转录和蛋白质组数据的生成 活组织检查；2)从患者来源的器官中配对的单细胞和批量转录和蛋白质组学；3)配对 转录组学和病人血液中的蛋白质组学。为了进一步了解这个数据集，我们将把这些 VEOIBD的深度免疫表型(通过质量细胞术)和功能特征的数据 病人衍生的有机化合物。在这项应用中，我们建议研究150-200名VEOIBD患者(6年)和30名- 40名年龄匹配的对照组，采用批量和单细胞RNA测序和蛋白质组学从活检和 配对的外周血样。此外，我们将对肠道活检组织进行深度免疫表型分析。 (75-100名患者；15-20名对照)配对的外周血，以及器官发育伴随着 100-150例VEOIBD患者和20-30例VEOIBD患者的批量和单细胞RNA测序及功能评估 控制。到目前为止，肠道中导致疾病病理的多种细胞类型主要是 以集合的形式进行研究。为了使组织内的细胞特异性信号解卷，并将疾病 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VEOIBD因果基因变体，这些基因变体不会 不仅使这些患者更好地了解了疾病，而且还促进了疾病的发展 VEOIBD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 图书馆的数据和有机化合物与科学界，以加快我们的使命，确定治疗 VEOIBD的目标和治疗方法。

项目成果

Human MD2 deficiency-an inborn error of immunity with pleiotropic features.

人类MD2缺乏症——一种具有多效性的先天性免疫缺陷。

• DOI: 10.1016/j.jaci.2022.09.033
• 发表时间: 2023
• 期刊: The Journal of allergy and clinical immunology
• 作者: Li,Yue;Yu,Ziqi;Schenk,Madlin;Lagovsky,Irena;Illig,David;Walz,Christoph;Rohlfs,Meino;Conca,Raffaele;Muise,AleixoM;Snapper,ScottB;Uhlig,HolmH;Garty,BenZion;Klein,Christoph;Kotlarz,Daniel
• 通讯作者: Kotlarz,Daniel