Discovering immune drivers of fibroblast polarization andrecovery in systemic sclerosis - PROJECT SUMMARY / ABSTRACT Background: This proposal is designed for Dr. Kimberly Lakin, MD, MS to grow toward becoming an independent investigator focused upon characterizing the clinical significance of immune cell-fibroblast associations in systemic sclerosis (SSc) skin. Currently, there are no approved treatments to manage both skin and internal organ fibrosis caused by systemic sclerosis (SSc), a deadly autoimmune disease with a complex and poorly understood pathophysiology involving inflammation and excess collagen production by skin fibroblasts. In clinical and trial settings, some patients improve, at times dramatically, while others do not, possibly related to distinct disease phases when cells are amenable (or not) to treatment. Reliable tools are needed to inform individualized treatment decisions and trial enrollment. Preliminary data by Dr. Lakin and her mentors suggest assessments of fibroblast activation status may yield such a tool. Preliminary data: Using paired biological (histology, gene expression) and clinical data from 24 individuals with diffuse cutaneous (dc)SSc, histologic assessments of two, inversely related fibroblast markers (aSMA, CD34) were associated with clinical severity and predicted the SSc inflammatory gene expression subset, using machine learning methods. Samples with inflammatory vs. non-inflammatory fibroblasts had increased B cells and type I interferon gene signature. A gene signature of fibroblast polarization (by aSMA/CD34) was computed and found to be higher at baseline in 52-week clinical improvers vs. non-improvers. Methods: Fine phenotype mapping of dcSSc (n=105), preSSc (Very Early Onset of SSc; n=12) and healthy (n=12) skin will be performed cross-sectionally. Immune pathways and cell types associated with activated fibroblasts will be evaluated by imaging mass cytometry (IMC), digital cell deconvolution, and histology. In a longitudinal analysis, baseline clinical and molecular features (histology scores; immune cell and fibroblast polarization signatures) will be tested as inputs in a model to predict 52 weeks clinical improvement. Career Development: The study goal is to unravel immune cell-fibroblast interactions in SSc and to test a histology-derived model for classifying patients most likely to clinically improve at one year. Dr. Lakin is an assistant attending physician at Hospital for Special Surgery (HSS) and assistant attending professor of medicine at Weill Cornell Medical College with access to the outstanding core services at these institutions. She will conduct patient-oriented research under the mentorship of Dr. Robert Spiera (HSS), an expert in SSc clinical research, and Dr. Dana Orange (Rockefeller), an expert in the use of bioinformatic approaches to discover patient subsets in rheumatic diseases. Dr. Lakin will engage in experiential and formal coursework to advance her bioinformatics, immunology, and skin imaging mass cytometry skills. This career development award will position Dr. Lakin for success in her objective to become an R01-funded independent investigator focused upon improving SSc patient care while uncovering key mechanisms of SSc pathogenesis.
