Mentoring in Translational Research in Interstitial Lung Diseases

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K24 Supplement Project Summary The purpose of this project is to provide a diverse, talented URM PhD the capacity to significantly expand her research program by elucidating the basic mechanisms by which metformin improves sarcoidosis lung function. Metformin has been shown to reduce lung fibrosis in bleomycin-treated murine models, and in a distinct investigation of diabetes patients, been demonstrated to alter the gut microbiome. We recently reported that alteration of the gut microbiome reduced lung fibrosis in murine models (manuscript under review). Review of the Vanderbilt electronic health record in sarcoidosis subjects suggests that metformin also leads to improved sarcoidosis forced vital capacity. The parent K24 involves a rigorous clinical investigation of the impact of metformin versus placebo on sarcoidosis lung function. Dr. Chioma will investigate for alteration in the gut microbiome among the enrolled patients. Implementation of this project will occur concomitantly with a randomized, placebo-controlled, double- blinded clinical trial of sarcoidosis subjects undergoing six months of treatment with either placebo or metformin. Stool collection will occur at baseline and each patient visit. Dr. Chioma will assess for changes in the stool microbiome among sarcoidosis patients randomized to metformin, compared to those randomized to placebo. She will perform a complementary investigation for alterations of the systemic T cell immunophenotype in each cohort. In addition, in order to obtain in vivo confirmation of the role of sarcoidosis gut microbial diversity on lung fibrosis severity, she will gavage germ-free mice with sarcoidosis stool slurry obtained at baseline and after metformin treatment, followed by intranasal bleomycin administration in order to assess for distinctions in lung fibrosis severity in murine models. These findings will enhance understanding of the mechanisms by which metformin impacts sarcoidosis lung function, while creating a distinct platform in which a talented, diverse URM PhD can further launch her career in academic medicine.