Pathogenesis and Therapy of Ulcerative Colitis - From Sequence to Mechanisms

炎症性肠病包括克罗恩病和溃疡性结肠炎，是一种慢性肠道疾病，但无法治愈。尽管新疗法的引入改善了整体生活质量，但仍有相当一部分患者的病程不令人满意。除了对发病机制有更好的了解外，尚未满足的需求包括对IBD亚型的详细剖析、对病程的预测以及病因和疾病特异性治疗。为了填补这一知识空白，我们正在新成立的合作研究中心项目“炎症性肠病中的免疫-上皮通讯；IBD中的IEC”的框架内开发一个集成平台，该平台将来自IBD患者的大规模基因组数据集与相应的临床疾病状态合并，称为IBDome。该数据库将在一个类似于已经建立的实体癌症平台的平台上实现，其中一个项目贡献者主要参与了该平台。这些数据将包括临床数据和生物医学信息，这些信息来自收集的肠道组织、外周血和粪便的综合分子特征，使用RNA测序、外显子组测序、16S微生物组测序、质量细胞术(飞行时间细胞术；CyTOF)和组织病理学。在该项目的框架内，我们目前正在为IBDome建立克罗恩病队列。然而，溃疡性结肠炎队列目前缺失。该项目的目的是通过纳入具有三个主要目标的溃疡性结肠炎队列来补充IBDome：i)提供对患有活动期和非活动期疾病的溃疡性结肠炎患者的深入分析，ii)确定溃疡性结肠炎与克罗恩病的鉴别机制和途径，以及iii)确定三种治疗策略的疗效预测因素，即肿瘤坏死因子-α抗体、抗整合素抗体(Vedolizumab)以及酪氨酸激酶抑制剂tofacitinib。集成的生物分子、成像和临床数据(疾病表型、疾病活动、药物、并发症)及其生物信息学分析将通过基于网络的前端提供给项目中的所有研究人员，以便进一步探索数据并生成可验证的假说。我们设想在项目过程中将IBDome进一步开发为IBD的参考数据库，其中将填充大量使用深度和广泛剖析进行分析的患者样本。因此，我们将不仅为该项目提供一个中央资源平台，也为科学界提供一个中央资源平台，从而加强翻译研究，使人们能够对IBD的发病机制有新的见解，并最终发现新的治疗策略。

Inflammatory bowel disease comprises Crohn's disease and ulcerative colitis and presents a chronic intestinal yet incurable disease group. Although the introduction of novel therapies has improved the overall quality of life, there is still a substantial subgroup with an unsatisfactory disease course. Besides a better understanding of the pathogenesis, unmet needs include the detailed dissection of IBD subtypes, the prediction of the disease course as well as causative and disease-specific therapies. In order to fill this knowledge gap, we are developing within the framework of the newly established Collaborative Research Center project "Immune-Epithelial Communication in Inflammatory Bowel Diseases; IEC in IBD" an integrated platform which merges large scale omic-datasets from IBD patients with corresponding clinical disease status, denoted IBDome. The database will be realized on a platform that is similar to already established platforms for solid cancers, where one of the project contributors was mainly involved in. The data will consist of clinical data and biomedical information derived from comprehensive molecular characterization of collected intestinal tissue, peripheral blood and stool using RNA sequencing, exome sequencing, 16s microbiome sequencing, mass cytometry (cytometry by time of flight; CyTOF), and histopathology. Within the framework of the project we are currently establishing a Crohn's disease cohort for IBDome. However, an ulcerative colitis cohort is currently missing. Aim of this project is to complement IBDome by including an ulcerative colitis cohort with three major aims: i) provide a yet lacking in-depth analysis of ulcerative colitis patients with active and inactive disease, ii) identify mechanisms and pathways discriminating ulcerative colitis from Crohn’s disease and iii) identify predictors of response for three treatment strategies, namely TNF-alpha antibodies, anti-integrin antibodies (vedolizumab) as well as the tyrosine kinase inhibitor tofacitinib. The integrated biomolecular, imaging, and clinical data (disease phenotype, disease activity, medication, complications) and its bioinformatics analyses will be made available through a web-based front-end to all researchers within the project in order to enable further exploration of the data and generation of testable hypotheses. We envision to further developing IBDome to a reference database for IBD during the course of the project, which will be populated with a large number of patient samples analyzed using both, deep and broad profiling. Hence, we will provide a central resource platform not only for the project but also for the scientific community and thereby strengthen translational research and enable novel insights into IBD pathogenesis and ultimately the discovery of novel therapeutic strategies.