GRADS Clinical Center: Studies in Sarcoidosis and Microbiomics Research

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，其病因和发病机制尚不完全清楚。宿主和环境因素都被认为参与其中。免疫学、基因表达和其他领域的新出现的科学方法为揭示这种疾病的新见解和确定潜在的新治疗方法提供了重要的希望。GRADS是一个多中心项目，用于招募受试者和收集生物标本，以实现这些技术的应用。我们小组参与了之前的几项结节瘤的多中心研究，在招募、临床表型和标本贡献方面都有明显的记录。我们项目的总体目标是 促进学科招募、高质量的表型鉴定和生物样品收集，以便通过毕业生联盟应用这些新技术。 相当多的证据表明，感染性触发因素与结节病的发病有关，但先前的研究尚未揭示或不一致。独立于培养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洞察。这些方法不需要培养能力或对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的复杂细菌和病毒种群。此外，通过呼吸道微生物学的一项新计划，我们开发了新的高精度采样、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，并展示了从分子上确定真正的下呼吸道微生物群落的能力，以及识别不同于上呼吸道或环境来源的独特肺部微生物的能力。我们的中心特定项目假设是，微生物制剂有助于结节病的发病机制，并可以通过使用严格的样本收集和新的生物信息学工具的独立于培养的分子方法进行鉴定。 这一建议反映了一种新的协同合作，它利用了校园内在临床研究和结节发病机制方面已建立的基础设施和专业知识(Rossman&Kreider)，以及最近在呼吸道微生物组研究方面建立的创新计划(Collman&Bushman)。我们的具体目标是：(1)招募新诊断的结节病患者进行详细的临床表型鉴定和高质量的生物标本收集，以实现财团范围的研究目标：(2)开展中心特定研究，以确定结节病下呼吸道(阶段2)中不依赖培养的微生物种群，并利用高严格的采样和焦磷酸测序方法，包括细菌16S核糖体rRNA基因、微真核生物rRNA基因和病毒元基因组方法；以及(3)参与指导委员会和NIH计划制定的广泛研究方案，如果得到小组目标的支持，通过GIC建立的程序，促进对财团范围样本的微生物组分析。 相关性：结节的原因尚不清楚，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，并找到新的治疗方法。我们参与了结节病的多中心研究，有良好的招募和标本捐赠记录，我们将招募受试者并为毕业生提供标本。许多证据表明，这可能是一种传染性触发因素，但之前的研究相互矛盾。新的分子微生物学方法使人体内微生物的研究发生了革命性的变化，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可能与结节病相关的感染性病原体。

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.