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

通过研究暴露组和基因组，利用多组学剖析 PSC 的发病机制和结果

• 批准号: 10246292
• 负责人: KONSTANTINOS N LAZARIDIS
• 金额: $ 150.51万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10246292
• 关键词: Accounting; Address; Age; Automobile Driving; Bile duct carcinoma; Biological; Blood; Chemical Exposure; Chemicals; Childhood; Cholangiocarcinoma; Cholestasis; Chronic; Clinic; Clinical; Clinical Data; Collaborations; Colon Carcinoma; Communities; DNA Methylation; DNA sequencing; Data; Data Analyses; Data Analytics; Diet; Disease; Environment; Environmental Exposure; Environmental Risk Factor; Epigenetic Process; Feces; Gene Expression; Generations; Genes; Genetic; Genetic Variation; Genome; Genomics; Goals; Graph; High Performance Computing; Illinois; Individual; Inflammatory Bowel Diseases; Institution; Life Style; Light; Link; Liver diseases; Machine Learning; Malignant Neoplasms; Mass Spectrum Analysis; Medical; Metagenomics; Microbe; Mission; Modeling; Molecular Disease; Multiomic Data; National Institute of Diabetes and Digestive and Kidney Diseases; Network-based; Norway; Onset of illness; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pesticides; Pharmaceutical Preparations; Phenotype; Pilot Projects; Positioning Attribute; Process; Research; Residual state; Resolution; Resources; Role; Science; Series; Shotguns; Specimen; Stress; Sum; Systems Biology; Taxonomy; Testing; Toxic Environmental Substances; Toxin; Universities; base; biobank; bioinformatics tool; clinical database; data integration; data resource; design; gene environment interaction; genome wide association study; genomic data; gut bacteria; gut metagenome; gut microbiota; improved; inflammatory disease of the intestine; innovation; liver transplantation; metabolome; metabolomics; metagenome; methylation pattern; methylome; methylomics; microbial; microbiome; multidisciplinary; multiple omics; novel; patient population; peripheral blood; personalized approach; pollutant; primary outcome; primary sclerosing cholangitis; programs; response; sex; toxin metabolism; transcriptome; transcriptomics; translational study

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.”

项目摘要/摘要 该RC2提案的主要目的是生成第一个多摩学翻译研究，以捕获 环境暴露的总和（即展示体）和主要数据资源的全面数据资源 硬化性胆管炎（PSC）是一种无效医疗治疗的慢性肝脏疾病。 PSC 缩短生存期，与炎症性肠病（IBD）有关，并且强烈倾向于 胆管癌（即胆管癌）和结肠癌。我们最近的基因组广泛研究 （GWAS）揭示了遗传变异在PSC中的重要作用，同时也重新强调了的重要性 PSC发病机理中的环境因素和基因环境相互作用。进一步阐明 来自我们外部环境和生活方式的暴露（例如饮食，压力，毒素，药物，微生物），我们有 组建了一个世界一流的多学科团队，该团队协同四个方面的专业知识和资源协同 机构：伊利诺伊大学Urbana-Champaign大学埃默里大学梅奥诊所（UIUC）和 奥斯陆大学，挪威。我们的协作团队将利用大型临床数据库和生物库， 以及PSC及相关条件，外汇学，代谢组学，甲基组学，转录组学的专业知识， 宏基因组学，基因组学和数据分析，以开发PSC科学社区资源 假设生成科学，仅发现导致PSC的因素。 我们现在寻求定义更大的细胞网络，而不是单个基因，驱动疾病 过程。为此，我们将使用旨在集成多层的公正基于网络的方法 OMICS数据。我们的建议预测了以下假设：多摩斯的数据捕获分析 环境暴露和相关的生物反应，包括对基因组的影响，将 揭示网络或途径会影响PSC的发病机理和结果。为了检验这一假设，我们将 执行一系列复杂的分析，以识别exposome和整个Exposome中与PSC相关的变化， 血液中的代谢组，甲基组和转录组以及肠道元素，杂物组和 代谢组。 我们的合作和数据生成已经进行了试点研究，证明 PSC患者和 控件。使用一套生物信息学工具和可用的遗传变异数据，我们旨在发现稳定的， 可检测的，基于OMIC的血液中的疾病特征（AIM 1）和凳子（AIM 2），当与 临床数据（AIM 3）将揭示驱动疾病发病机理和结果的生物学途径。所有数据， 剩余标本和分析细节将免费提供给研究社区的 因此，Niddk的使命。此外，这种努力对Niddk的呼吁做出了回应，以“更好 了解微生物组，遗传学和外博的作用。”