Our laboratory effort is focused on understanding scleroderma (systemic sclerosis), and developing novel therapeutic approaches based on identifying biomarkers of the disease process and utilizing biomarkers in clinical trials. We have utilized a biomarker approach in a clinical trial of fresolimumab (anti-TGF-beta) to show a role for TGF-beta in skin fibrosis associated with systemic sclerosis. More recently, we have applied single cell technologies to understand the molecular changes in stromal and inflammatory cell populations in the skin and lungs of patients with systemic sclerosis. In the skin we have discovered changes in several fibroblast populations. One of these populations, DPP4/SFRP2-expressing fibroblasts differentiate in two steps into myofibroblasts. In ongoing studies, we are identifying the alterations in chromatin structure and transcription factors regulating myofibroblast differentiation. We have carried out similar studies analyzing lungs from patients with systemic sclerosis associated interstitial lung disease. These lungs also show an emergent population of myofibroblasts, with an overlapping but distinct phenotype compared to skin myofibroblasts. We have also characterized a population of macrophages associated with progressive interstitial lung disease. We are further studying the pathways driving differentiation of both of these cell populations using single cell ATAC-seq. We anticipate that these detailed molecular understandings and in further in silico analysis in collaboration with colleagues in systems biology will lead us to better understand the cytokines communicating between cell populations promoting fibrosis, and lead to new key targets for therapeutic intervention.