GRADS Clinical Center: Studies in Sarcoidosis and Microbiomics Research

GRADS 临床中心：结节病和微生物组学研究

• 批准号: 8464263
• 负责人: Ronald G Collman
• 金额: $ 15.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464263
• 关键词: Address; Animal Disease Models; Area; Bacteria; Beryllium; Bioinformatics; Biological; Biomass; Blood; Clinical; Clinical Research; Collaborations; Collection; Complex; Detection; Disease; Enrollment; Environmental Risk Factor; Etiology; Face; Fibrosis; Gene Expression; Genes; Genital system; Genomics; Goals; Granulomatous; Health; Human; Immune response; Immunologics; Immunology; Infectious Agent; Inflammation; Inflammatory; Informatics; Integration Host Factors; Investigation; Knowledge; Laboratories; Link; Lower respiratory tract structure; Lung; Metagenomics; Methods; Microbe; Microbiology; Molecular; Multicenter Studies; Nature; Newly Diagnosed; Oral cavity; Organ Transplantation; Pathogenesis; Phenotype; Population; Procedures; Protocols documentation; Recruitment Activity; Reporting; Research; Research Infrastructure; Respiratory Failure; Respiratory System; Respiratory tract structure; Role; SAGA; Sampling; Sarcoidosis; Site; Skin; Smoking; Source; Specimen; Staging; Support Groups; T-Lymphocyte; Techniques; Tissues; United States National Institutes of Health; Upper respiratory tract; Viral; Virus; base; clinical phenotype; density; innovation; insight; lung injury; macrophage; microbial; microbiome; mycobacterial; new technology; novel; novel strategies; programs; pyrosequencing; rRNA Genes; sample collection; tool; transcriptomics; transmission process; virome

DESCRIPTION (provided by applicant): Sarcoidosis is a granulomatous inflammatory disease of great clinical importance, yet its etiology and pathogenesis remain incompletely understood. Both host and environmental factors are believed to be involved. Newly emerging scientific approaches in immunology, gene expression and other areas offer significant promise to reveal new insight into the disease and identify potential new treatments. GRADS is a multicenter program for recruitment of subjects and biospecimen collection to enable application of these techniques. Our group has been involved in several previous multicenter studies of sarcoid, with a demonstrated record of recruitment, clinical phenotyping, and specimen contribution. The overall goal of our project is to contribute to subject recruitment, high quality phenotyping and biospecimen collection for applying these new technologies through the GRADS consortium. Considerable evidence implicates an infectious trigger in sarcoid pathogenesis, but prior studies have been unrevealing or inconsistent. Recent advances in culture-independent molecular microbiology are revealing unexpected insights into complex microbial populations and their nature in human health and disease. These approaches do not require ability to culture or a priori knowledge of microbial agents. Our group has pioneered the use of these approaches to define complex bacterial and viral populations in gut and blood. In addition, through a new program in respiratory tract microbiomics, we have developed novel high stringency sampling, analytic and bioinformatic approaches to overcome important challenges in applying these approaches to the lung, and demonstrated the ability to molecularly define genuine lower respiratory tract microbial inhabitants, and identify unique lung microbes distinct from upper respiratory tract or environmental sources. Our center-specific project hypothesis is that microbial agents contribute to the pathogenesis of sarcoidosis and can be identified through culture-independent molecular approaches utilizing stringent sample collection and novel bioinformatic tools. This proposal reflects a new, synergistic collaboration that takes advantage of established infrastructure and expertise on campus in clinical research and sarcoid pathogenesis (Rossman & Kreider) and a recently-established innovative program in respiratory tract microbiome studies (Collman & Bushman). Our specific aims are to: (1) Enroll subjects with newly diagnosed sarcoidosis for detailed clinical phenotyping and high quality biospecimen collection for consortium wide study goals: (2) Carry out a center-specific study to define the culture-independent microbial populations in the lower respiratory tract of sarcoid (stage 2) and control subiects utilizing high stringency sampling and pyrosequencing including bacterial 16S ribosomal rRNA gene, microeukaryote rRNA gene and virome metagenomic approaches; and (3) Participate in study-wide protocols as developed by the Steering Committee and NIH program and, if supported by group goals, facilitate microbiome analysis on consortium-wide samples via procedures established through the GIC. RELEVANCE: The cause of Sarcoid is unknown but new approaches in immunology, gene expression and other areas may reveal new insight and identify new treatments. We have been involved in multicenter studies of sarcoid with a strong record of recruitment and specimen contribution, and we will recruit subjects and contribute specimens for GRADS. Many lines of evidence suggest a possible infectious trigger, but prior studies are contradictory. New molecular microbiology approaches have revolutionized studies of microbes in the body, and our group has pioneered their application to the lung. Our Center Project will apply this new technology to identify possible infectious agents associated with sarcoid.

描述（由申请人提供）： 结节病是一种具有重要临床意义的肉芽肿性炎症性疾病，但其病因和发病机制仍不完全清楚。据信宿主和环境因素都参与其中。免疫学、基因表达和其他领域新兴的科学方法为揭示对该疾病的新见解和确定潜在的新疗法提供了重大希望。 GRADS 是一个多中心计划，用于招募受试者和收集生物样本，以实现这些技术的应用。我们的小组之前参与了几项结节病的多中心研究，并在招募、临床表型和标本贡献方面有良好的记录。我们项目的总体目标是 通过 GRADS 联盟为受试者招募、高质量表型分析和生物样本收集做出贡献，以应用这些新技术。 大量证据表明结节病发病机制中存在感染触发因素，但之前的研究尚未揭示或不一致。独立于培养物的分子微生物学的最新进展揭示了对复杂微生物种群及其在人类健康和疾病中的性质的意想不到的见解。这些方法不需要培养能力或微生物制剂的先验知识。我们的团队率先使用这些方法来定义肠道和血液中复杂的细菌和病毒种群。此外，通过呼吸道微生物组学的新计划，我们开发了新颖的高严格采样、分析和生物信息学方法，以克服将这些方法应用于肺部的重要挑战，并证明了从分子水平上定义真正的下呼吸道微生物居民的能力，并识别出不同于上呼吸道或环境来源的独特肺部微生物。我们中心特定的项目假设是，微生物制剂有助于结节病的发病机制，并且可以通过利用严格的样本收集和新颖的生物信息学工具的独立于培养的分子方法来识别。 该提案反映了一种新的协同合作，利用校园内临床研究和结节病发病机制（Rossman & Kreider）方面的现有基础设施和专业知识，以及最近建立的呼吸道微生物组研究创新项目（Collman & Bushman）。我们的具体目标是：(1) 招募新诊断的结节病受试者进行详细的临床表型分析和高质量生物样本收集，以实现联盟范围内的研究目标：(2) 开展一项中心特定研究，以确定结节病下呼吸道中的培养独立微生物种群（第 2 阶段），并利用高严格采样和焦磷酸测序（包括细菌 16S）控制受试者 核糖体rRNA基因、微型真核生物rRNA基因和病毒组宏基因组方法； (3) 参与指导委员会和 NIH 计划制定的研究范围协议，如果得到团体目标的支持，通过 GIC 建立的程序促进对联盟范围样本的微生物组分析。 相关性：结节病的病因尚不清楚，但免疫学、基因表达和其他领域的新方法可能会揭示新的见解并确定新的治疗方法。我们一直参与结节病的多中心研究，在招募和标本贡献方面拥有良好的记录，我们将为 GRADS 招募受试者并贡献标本。许多证据表明可能存在传染性触发因素，但之前的研究是相互矛盾的。新的分子微生物学方法彻底改变了体内微生物的研究，我们的团队率先将其应用于肺部。我们的中心项目将应用这项新技术来识别与结节病相关的可能的传染源。