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.