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.