PROJECT SUMMARY Pulmonary involvement occurs in up to 90% of sarcoidosis cases, the disease course is heterogeneous and respiratory failure is the leading cause of sarcoidosis-related mortality in the US. Most studies undertaken to date in sarcoidosis compare cases to healthy or disease controls. There are knowledge gaps in the understanding of sarcoidosis subtypes including the underlying molecular features, biologic pathways and mechanisms of progressive pulmonary sarcoidosis disease progression. As a result, there are no clinical tools available for early prediction of progressive (P) sarcoidosis to allow closer clinical follow-up, early treatment and to provide focus for research. The goal of this project is to enroll sarcoidosis patients to define molecular characteristics of P- sarcoidosis that will (a) enable early identification of patients at higher risk of progression. To develop tools for rapid identification and prediction of P-sarcoidosis progression, this project will investigate molecular signatures (proteins and genes ) and related biological pathways identified in a laboratory model of sarcoidosis granulomas and in peripheral blood mononuclear cells (PBMCs) of patients with P- vs non-progressive (NP)- sarcoidosis. (b) provide insights into the different biological mechanisms driving outcomes in pulmonary sarcoidosis. Our promising pilot data identified protein and transcriptional pathways engaged during granulomatous inflammation and in PMBCs in proxies of P- and NP-sarcoidosis. Aim 1 builds on preliminary findings, characterizing differences in P- and NP-sarcoidosis protein and gene pathways, leveraging the unique granuloma model. We include single cell-RNA-Sequencing in a subset of cases with innovative digital cytometry methods to obtain cell- specific pathways. Aim 2 will define pathways and signatures from PBMCs, which are recruited and contribute to granuloma development and persistence as well as features that are shared and distinct from the model. Aim 3 will leverage findings from PMBCs and the in vitro model and clinical disease manifestations using innovative bioinformatics approaches to construct and internally validate a comprehensive classifier that incorporates proteins, clinical variables and patient-reported outcomes in a Discovery Cohort. The investigators will validate this classifier in an independent Validation Cohort of subjects already enrolled by the research team in prior NIH funded studies. The study uses novel approaches to characterize P-sarcoidosis and a diverse research team led by MPIs with complementary expertise. The integration of sarcoidosis investigators from different locations across the country will advance and sustain the sarcoidosis research through highly innovative translational studies implementing state-of-the-art clinical and biological systems-level studies in a high-priority area of research in sarcoidosis. These studies will provide the foundation for future studies aimed at evalua...