Functional Genomics Core

功能基因组学核心

• 批准号: 10024958
• 负责人: Anthony Haag
• 金额: $ 73.95万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10024958
• 关键词: 16S ribosomal RNA sequencing; Adopted; Affect; Antibiotics; Antimicrobial Resistance; Back; Bacterial Chromosomes; Bar Codes; Biometry; Cancer Center; Centers for Disease Control and Prevention (U.S.); Clinical; Clostridium difficile; Complex; Coupled; Critical Illness; DNA; DNA sequencing; Data; Data Analyses; Data Storage and Retrieval; Databases; Development; Disease; Disease Progression; Disease susceptibility; Documentation; Enterobacteriaceae; Equipment and supply inventories; Extended-spectrum β-lactamase; Feces; Foundations; Freezing; Generations; Genes; Genome; Genomics; Goals; Hospitals; Immunocompromised Host; Individual; Infection; Institution; Intensive Care Units; Laboratories; Maintenance; Maps; Medical center; Metabolic; Metagenomics; Microbiology; Modeling; Multiomic Data; Outcome; Patients; Plasmids; Positioning Attribute; Predisposition; Process; Program Research Project Grants; Protein Analysis; Proteins; Public Health; Resources; Risk Factors; Sampling; Sampling Studies; Shotgun Sequencing; Shotguns; Site; Societies; Source; Statistical Methods; Stem cell transplant; Texas; United States National Institutes of Health; University of Texas M D Anderson Cancer Center; Vancomycin resistant enterococcus; bacterial genome sequencing; bioinformatics infrastructure; bioinformatics pipeline; carbapenemase; cohort; computerized data processing; data format; dysbiosis; functional genomics; genome sequencing; gut colonization; gut microbiome; interest; metabolome; metabolomics; metagenomic sequencing; metaproteomics; microbial; microbiome; microbiota; multi-drug resistant pathogen; multiple omics; novel; pathogen; programs; small molecule; stool sample; tool; whole genome

ABSTRACT (Functional Genomics Core) Antimicrobial resistance (AMR) and its impact have been recognized by the WHO, CDC, FDA, and NIH as one of the most important public health threats facing society today. Vancomycin-resistant enterococci (VRE), extended spectrum β-lactamase/carbapenemase-producing Enterobacteriaceae (ESBL-E/CRE), and Clostridiodes difficile are of particular interest as they disproportionately affect immunocompromised and severely ill patients. The CDC has designated VRE as a serious threat and both ESBL-E/CRE and C. difficile as urgent threats. Each of these pathogens is able to colonize and infect the gut, with disruption of the protective gut microbiome by antibiotics a leading risk factor for infection. The overarching hypothesis of the DYNamics of colonizAtion and infection by Multidrug-resIstant paThogens in immunocompromisEd patients program (DYNAMITE) is that patient susceptibility to nosocomial acquisition, gut colonization, and subsequent infection by pathogens is critically dependent on functional microbiota-pathogen interactions that determine disease progression and clinical outcomes. Importantly, we posit that shotgun metagenomics data coupled with inferred metabolic potential is not enough to predict and interpret susceptibility to colonization and infection in a dysbiotic patient, and a combination of genomics, metagenomics, metabolomics, and metaproteomics is necessary to elucidate the complex interplay between the pathogen, the microbiome, and the host. To enable this multi-omic approach, the Functional Genomics Core (FGC) will provide a central resource to all three projects contained within this application, providing facilities and expertise for whole genome sequencing, metagenomics, metaproteomics, and metabolomics. Additionally, leveraging the robust bioinformatics infrastructure housed within the FGC, we will provide the application of existing analytical pipelines and disease classifiers–as well as the development of novel pipelines—that will integrate and facilitate the comprehensive analyses of the data generated for each individual project. As an example, we have built a high-throughput pipeline for the generation and annotation of reference-quality fully circularized bacterial chromosomes and accompanying plasmids, and with accompanying metaproteomics data have mapped 92% of protein signatures back to the source gene. Overall, to achieve the scientific goals outlined in this P01 application, the FGC will undertake three aims: i) coordinate the transfer of pure microbiological isolates and patient stool samples from the study sites to the FGC; ii) complete genomic, metagenomic, metaproteomic, and metabolomic processes of each project; and iii) assist in the analysis and integration of the multi-omic data generated under each project. The FGC provides a unique and unparalleled ability to combine multiple omics data types to create a truly multi-omic assessment of the complex interplay between VRE, ESBL-E/CRE, and C. difficile, the gut microbiome, and the host metabolome, facilitating the goals of this DYNAMITE program.

摘要（功能基因组学核心） WHO，CDC，FDA和NIH已认可抗菌抗性（AMR）及其影响 当今社会面临的最重要的公共卫生威胁。抗性霉素肠球菌（VRE）， 扩展的光谱β-内酰胺酶/碳纤维烯酶产生的肠杆菌科（ESBL-E/CRE）和 梭状芽胞杆菌艰难梭菌特别关注，因为它们不成比例地影响免疫功能低下和 严重患者。 CDC将VRE指定为严重威胁，ESBL-E/CRE和C.艰难梭菌 作为紧急威胁。这些病原体中的每一个都能够在肠道上定植并感染肠道，并破坏 抗生素保护性肠道微生物组是感染的主要危险因素。总体假设 免疫功能低下患者中多药耐药病原体的定殖和感染动力学 程序（炸药）是患者对医院习得，肠道化和随后的敏感性 病原体感染至关重要的取决于确定的功能性微生物群 - 病原体相互作用 疾病的进展和临床结果。重要的是，我们的海报shot弹枪宏基因组学数据耦合 具有推断的代谢潜力不足以预测和解释殖民化的易感性和 不植物患者的感染以及基因组学，宏基因组学，代谢组学和 元蛋白质组学对于阐明病原体，微生物组和 主人。为了启用这种多摩变方法，功能基因组学核心（FGC）将提供中心 为本应用程序中包含的所有三个项目的资源，为整体提供了设施和专业知识 基因组测序，宏基因组学，元蛋白质组学和代谢组学。另外，利用强大的 在FGC中包含的生物信息学基础设施，我们将提供现有分析的应用 管道和疾病分类器（以及新型管道的发展）将整合和 促进对每个项目生成的数据的全面分析。例如，我们 已经建立了一条高通量管道，用于产生和注释参考质量完全循环 细菌染色体和参与的质粒，并且随着参与的元蛋白质组学数据具有 将92％的蛋白质特征映射回源基因。总的来说，要实现概述的科学目标 该P01应用程序，FGC将实现三个目的：i）协调纯微生物的转移 从研究地点到FGC的分离株和患者粪便样品； ii）完全基因组，宏基因组学 每个项目的元蛋白质组学和代谢组过程； iii）协助分析和集成 每个项目下生成的多摩尼克数据。 FGC提供了独特且无与伦比的能力 结合多种OMIC数据类型，以创建对复杂相互作用的真正多摩变评估 VRE，ESBL-E/CRE和艰难梭菌，肠道微生物组和宿主代谢组，促进了目标的目标 炸药程序。