Integrated Genomics of Mucosal Infections

整体项目总结 此应用程序请求为德克萨斯医疗中心的传染病基因组学中心(GCID)提供资金 该中心(TMC)由贝勒的基础和内科科学家组成的多学科综合团队组成 医学院、德克萨斯大学-休斯顿公共卫生学院和MD安德森癌症中心。 我们GCID的总体目标是：i)利用我们几十年来在基因组测序方面的经验 技术与我们著名的临床专业知识，并使用新的体外器官模型 人体肠道和肺功能，打造以大规模基因组学为基础的平台 在人类组织的背景下询问宿主-粘膜病原体的相互作用，以及ii)利用这一点 基于宿主和微生物的发现新的治疗和诊断靶点的平台 基因组和转录组图谱。项目1(PL：A.Maresso，PhD)将剖析 赋予肠杆菌科和肠球菌科的致病成员与 同时也确定了宿主对这种联系的反应。项目2(PL：M.Estes， PHD)将利用对人类诺如病毒和呼吸道合胞病毒全长基因组的综合分析 临床相关患者亚群样本的生态位序列和特征 对病毒复制、重组和进化、疾病诱发和宿主因素的新认识 感染易感性和致病机制所必需的。项目3(PL：D.Corry，MD)将测试假设 真菌多样性、致病力和个体对真菌负担的先天免疫反应是持久的、 治疗难治性中重度哮喘--呼吸道真菌负荷的新范例 呼吸道真菌病(“呼吸道真菌病”)可能在过敏性肺部炎症的发展和持续中起到致病作用。 项目4(PL：P.Okhuysen，MD)将建立在项目负责人发现的新隐孢子虫的基础上 并测试一种假设，即肠道中一种或多种产生吲哚的共生微生物可以防止或 消除隐孢子虫感染。所有四个研究项目都将利用人体肠道和肺的有机物质 培养以及由有机物和微型生物反应器提供的特定于生态位的微生物群落 阵列培养核心和大量独特的临床样本和分离株，结合了尖端技术， 由测序技术(ST)核心提供的高通量测序策略和技术。 改变范式的发现、数据、工具和试剂将传播到传染病社区 由数据管理分析和资源传播(DMARD)核心通过最先进的门户 由DNANXUS开发。其结果将是对人类宿主和微生物的全面遗传图谱 感染模型将揭示病原体的遗传变异，并告知个别宿主的反应表型 基于精确医学的治疗和诊断，既针对本提案中的病原体，也针对广泛的 严重影响人类健康的一系列粘膜传染病。

Overall Project Summary This application requests funding for a Genomics Center for Infectious Disease (GCID) in the Texas Medical Center (TMC) that comprises a multidisciplinary, integrated team of basic and physician scientists at Baylor College of Medicine, the University of Texas-Houston School of Public Health, and MD Anderson Cancer Center. The overall goal of our GCID is to: i) leverage our decades of experience in genomic sequencing technology with our renowned clinical expertise, and the use of novel ex vivo organotypic models of human intestinal and pulmonary function, to create a platform for large scale genomics-based interrogation of host-mucosal pathogen interactions in the context of human tissues, and ii) utilize this platform for the discovery of novel therapeutic and diagnostic targets based on host and microbial genomic and transcriptomic profiles. Project 1 (PL: A. Maresso, PhD) will dissect the genomic elements that confer the ability of pathogenic members of the Enterobacteriaceae and Enterococcaceae to associate with the human intestinal mucosa while also determining the host response to this association. Project 2 (PL: M. Estes, PhD) will leverage integrated analyses of human norovirus and respiratory syncytial virus full-length genomic sequences and characterization of the ecological niche of samples from clinically relevant patient sub-groups for new understanding of viral replication, recombination and evolution, induction of disease and host factors required for susceptibility to infection and pathogenesis. Project 3 (PL: D. Corry, MD) will test the hypothesis that fungal diversity, virulence, and individual innate immune responses to fungal burdens underlie persistent, treatment-resistant moderate to severe asthma in a new paradigm whereby fungal burden within the respiratory tract (“airway mycosis”) may have a causative role in development and persistence of allergic lung inflammation. Project 4 (PL: P. Okhuysen, MD) will build on a novel Cryptosporidium discovery made by the project leaders and test the hypothesis that one or more indole-producing commensal microbes in the gut can prevent or eliminate Cryptosporidium infection. All four research projects will utilize human intestinal and lung organoid cultures along with niche-specific, defined microbial communities supplied by the Organoid and Minibioreactor Array Cultivation Core and a large collection of unique clinical samples and isolates, incorporating cutting edge, high-throughput sequencing strategies and technologies supplied by the Sequencing Technology (ST) Core. Paradigm-shifting discoveries, data, tools, and reagents will be disseminated to the infectious disease community by the Data Management Analysis and Resource Dissemination (DMARD) Core through a state of the art portal developed by DNAnexus. The result will be a comprehensive genetic profiling of hosts and microbes in human infection models that will reveal pathogen genetic variants, and individual host response phenotypes to inform precision medicine-based therapeutics and diagnostics, both for the pathogens in this proposal and a broad spectrum of mucosal infectious diseases that severely impact human health.