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. We are also applying our pharmacodynamic biomarker of skin disease to trials of tocilizumab (trial completed), and C-82 and rilonacept (ongoing). Our group has particular interest in understanding the mechanisms stimulating immune response in systemic sclerosis, focusing on innate immune responses leading to fibrosis and vascular injury. Our data show increased expression of interferon responsive genes in circulating monocytes of scleroderma patients, prompting current investigations into the stimulus for this pattern of gene expression and the effect of interferon on fibrosis and vascular injury. Most recently, we have been examining the transcriptome of single cells in the skin and lungs of patients with systemic sclerosis to better understand changes in gene expression in different immune and connective tissue cell types that lead to disease.

 

To aid in developing new therapies for systemic sclerosis, we are studying the pathogenesis through existing murine models, particularly bleomycin-induced skin and lung fibrosis, testing novel therapeutics to clarify the relationship between innate immunity and fibrosis. Our goal is to gain insight from these models that will enable us to propose more informative early phase clinical trials, utilizing biomarkers to show target engagement and as a surrogate clinical response.