Investigating the role of A20 and DREAM in adipogenesis and systemic sclerosis

PROJECT SUMMARY The pathogenesis of systemic sclerosis (SSc) is not well understood, and effective treatments are lacking. A unifying fibrosis paradigm is myofibroblast plasticity, by which quiescent resident myofibroblasts transform into activated myofibroblasts during fibrosis development. Key interactions between vascular changes and early immunological alterations occurs early in the course of disease. Loss of dermal white adipose tissue (dWAT) is another major clinical manifestation of SSc skin fibrosis. Resident mature adipocytes are lost in human and mouse skin tissues at early stage of fibrosis, yet the mechanisms that drive loss of mature adipocytes and their contribution to tissue fibrosis are unknown. In this proposal, we will examine the role of A20 in endothelial and adipocyte-specific differentiations to myofibroblasts (Endo-MT and AMT), and how attenuation of A20 in SSc patients promotes fibrosis initiation and progression, and/or retards its resolution. We will use scRNA-seq analysis to identify genes and pathways differentially regulated during Endo-MT and AMT and will correlate with SSc sc-RNA-seq dataset to examine their contribution to early stage SSc. A20 repressor DREAM by binding to A20 promoter suppress its expression. We will explore how by pharmacological/genetic approaches to increase endogenous A20 function/expression by controlling DREAM will limit adverse tissue remodeling, opening the door to novel therapeutic strategies. The project is of high impact since there are no appropriate treatments for SSc. Moreover, the results will have a strong impact on myriad fibrosing diseases that currently lack effective treatment.