Dissecting the pathogenesis and outcomes of PSC using multi-omics by studying the exposome and genome

项目摘要/摘要 这个RC2提案的主要目标是生成第一个多组学翻译研究，该研究捕获了 初级环境暴露总量(即曝光组)和综合数据资源 硬化性胆管炎(PSC)是一种慢性进行性肝病，没有有效的药物治疗。PSC 缩短生存期，与炎症性肠病(IBD)相关，并极易患上 胆管癌(即胆道癌)和结肠癌。我们最新的全基因组关联研究 (Gwas)揭示了遗传变异在PSC中的重要作用，同时也再次强调了 环境因素和基因-环境相互作用在PSC发病中的作用。以进一步阐明其作用 暴露于我们的外部环境和生活方式(例如，饮食、压力、毒素、药物、微生物)，我们有 组建了一支世界级的多学科团队，整合了四个领域的专业知识和资源 机构：梅奥诊所、埃默里大学、伊利诺伊大学香槟分校(UIUC)和 挪威奥斯陆大学。我们的协作团队将利用大型临床数据库和生物信息库， 以及在PSC和相关条件、暴露组学、代谢组学、甲基组学、转录组学、 元基因组学、基因组学和数据分析，以开发PSC科学社区资源 产生假设的科学，并同时发现促成PSC的因素。 我们现在试图定义驱动疾病的更大的细胞网络，而不是单个基因 流程。为此，我们将使用基于网络的无偏见方法，旨在集成多层 组学数据。我们的建议是基于这样一个假设，即数据捕获的多组学分析 环境暴露和相关的生物反应，包括对基因组的影响，将 揭示影响PSC发病机制和预后的网络或途径。为了检验这一假设，我们将 执行一系列复杂的分析以识别曝光组中和跨曝光组的与PSC相关的变化， 血液中的代谢组、甲基组和转录组以及肠道的元基因组、曝光组和 代谢体。 我们的合作和数据生成已经在进行中，试点研究表明 PSC与PSC患者血液暴露组、代谢组和粪便代谢组的差异 控制。使用一套生物信息学工具和可用的遗传变异数据，我们的目标是发现稳定的、 血液(目标1)和粪便(目标2)中可检测的基于组学的疾病特征，与 临床数据(目标3)将揭示驱动疾病发病机制和结果的生物途径。所有数据， 剩余样本和分析细节将在#年免费提供给研究界。 符合NIDDK的使命。此外，这一努力响应了NIDDK的号召： 了解微生物组、遗传学和曝光组的作用。

PROJECT SUMMARY/ABSTRACT The major goal of this RC2 proposal is to generate the first, multi-omics translational study capturing the sum of environmental exposures (i.e. the exposome) and comprehensive data resource for Primary Sclerosing Cholangitis (PSC), a chronic, progressive liver disease without effective medical therapy. PSC shortens survival, is associated with inflammatory bowel disease (IBD) and strongly predisposes to cholangiocarcinoma (i.e. bile duct cancer) and colon cancer. Our recent genome wide association studies (GWAS) revealed the significant role of genetic variation in PSC, while also re-emphasizing the importance of environmental factors and gene-environment interactions in PSC pathogenesis. To further elucidate the role of exposures from our external environment and lifestyle (e.g., diet, stress, toxins, drugs, microbes), we have assembled a world-class, multi-disciplinary team that synergizes expertise and resources across four institutions: Mayo Clinic, Emory University, University of Illinois Urbana-Champaign (UIUC), and University of Oslo, Norway. Our collaborative team will leverage large clinical databases and biorepositories, as well as expertise in PSC and related conditions, exposomics, metabolomics, methylomics, transcriptomics, metagenomics, genomics, and data analytics to develop the PSC Scientific Community Resource for hypothesis-generating science and simultaneously uncover factors contributing to PSC. We now seek to define the bigger-picture cellular networks, rather than individual genes, driving disease processes. To do so, we will use unbiased network-based approaches designed to integrate multiple layers of omics data. Our proposal is predicated on the hypothesis that multi-omics analyses of data capturing environmental exposures and the associated biological responses, including the effect on the genome, will reveal networks or pathways influencing PSC pathogenesis and outcomes. To test this hypothesis, we will perform a series of sophisticated analyses to identify PSC-associated changes in and across the exposome, metabolome, methylome, and transcriptome in blood as well as the gut metagenome, exposome and metabolome. Our collaboration and data generation are already underway with pilot studies demonstrating differences in blood exposomes and metabolomes and stool metagenomes between PSC patients and controls. Using a suite of bioinformatic tools and available genetic variation data, we aim to discover stable, detectable, omics-based disease signatures in blood (Aim 1) and stool (Aim 2) that when integrated with clinical data (Aim 3) will reveal biological pathways driving disease pathogenesis and outcomes. All data, residual specimens, and analytical details will be made freely available to the research community in accordance with NIDDK's mission. Furthermore, this effort responds to the NIDDK's call “to better understand the role of the microbiome, genetics, and exposome.”