Pathogenesis and Therapy of Ulcerative Colitis - From Sequence to Mechanisms

溃疡性结肠炎的发病机制和治疗——从序列到机制

• 批准号: 418055832
• 负责人: Professor Dr. Christoph Becker
• 金额: --
• 依托单位: Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/418055832?language=en
• 关键词: Pathogenesis; Therapy; Ulcerative; Colitis; Sequence

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.

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。虽然新疗法的引入改善了整体生活质量，但仍有相当一部分亚组的病程不令人满意。除了更好地了解发病机制外，未满足的需求还包括IBD亚型的详细解剖，疾病过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-上皮细胞通讯; IBD中的IEC”的框架内开发一个集成平台，该平台将IBD患者的大规模组学数据集与相应的临床疾病状态合并，表示为IBDome。该数据库将在一个平台上实现，该平台类似于已经建立的实体癌平台，其中一个项目贡献者主要参与其中。数据将包括临床数据和生物医学信息，这些信息来自于使用RNA测序、外显子组测序、16 s微生物组测序、质谱细胞术（飞行时间细胞术; CyTOF）和组织病理学对收集的肠组织、外周血和粪便进行的综合分子表征。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溃疡性结肠炎队列来补充IBDome，其主要目的有三个：i）提供对患有活动性和非活动性疾病溃疡性结肠炎患者的尚缺乏的深入分析，ii）鉴定区分溃疡性结肠炎与克罗恩病的机制和途径，和iii）鉴定三种治疗策略的响应的预测因子，即TNF-α抗体，抗整联蛋白抗体（Vedolizumab）以及酪氨酸激酶抑制剂托法替尼。整合的生物分子，成像和临床数据（疾病表型，疾病活动，药物治疗，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内的所有研究人员，以便进一步探索数据并生成可验证的假设。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，该数据库将使用深度和广泛分析的大量患者样本进行填充。因此，我们将不仅为该项目，而且为科学界提供一个中心资源平台，从而加强转化研究，使人们对IBD发病机制有新的见解，并最终发现新的治疗策略。