Project Summary The overall goal of this renewal application for a MidCareer Investigator Award in Patient-Oriented Research is to enable the candidate to continue to expand her research and mentoring programs in sarcoidosis patient- oriented research. This award will allow her to continue to devote significant protected time to the professional development of her current mentees with a focus on successful transition to scientific independence. During the prior award period, the candidate and her mentees identified a crucial role for the Programmed Death-1/STAT3 signaling pathway in Th17 cells to pulmonary sarcoidosis progression. Now this team provides compelling preliminary data that metformin reduces the percentage of sarcoidosis PD-1+CD4+ T cells in vitro, and that this reduction is associated with reduced human lung fibroblast (HLF) collagen production. In this renewal application, Dr. Drake and her mentees will assess the capacity of oral metformin to alter PD-1 expression on sarcoidosis CD4+ T cells in vivo, as well as identify relevant mechanisms by which this occurs. The team will determine the impact of oral metformin on sarcoidosis forced vital capacity (FVC), focus on Th17 cell immuno- metabolomic alterations, as well as alterations in STAT3 signaling. The two specific aims are as follows: 1) To assess the in vivo efficacy of oral metformin on reduction of PD-1+CD4+ T cells in sarcoidosis subjects and its impact on sarcoidosis FVC; 2) To assess if oral metformin has the capacity to reduce HLF collagen production in sarcoidosis subjects. These translational investigations will lay a firm foundation for a future advanced clinical investigation of metformin efficacy against pulmonary sarcoidosis progression. The results from the proposed clinical and mechanistic investigations will be translated into advanced clinical trials, thus providing future mentees with basic, translational and clinical platforms for their career development.