DESCRIPTION (provided by applicant): Fibrosis in scleroderma results from accumulation of activated myofibroblasts in injured microenvironments, and is accompanied by loss of subcutaneous adipose tissue. Since myofibroblast differentiation is potentially reversible, understanding signaling pathways and transcription molecules controlling the process is of fundamental importance for the development of antifibrotic therapies. The master regulator of adipogenesis, PPAR-gamma, is a potent inhibitor of myofibroblast differentiation in multiple organs. We found that the inhibitory effects are mediated through adiponectin (ADP), an adipokine with pleiotropic humoral and paracrine effects produced primarily but not exclusively by fat cells. Levels of ADP were significantly reduced in skin biopsies and in serum from patients with early diffuse scleroderma. These observations suggest a novel paradigm for fibrosis linking impaired adipogenesis, reduced ADP production and unchecked myofibroblast differentiation. Our hypothesis is that adipose atrophy and consequent hypoadiponectinemia contribute to persistent fibrogenesis in scleroderma. We predict that ADP and first-in-class synthetic peptides acting as ADP receptor agonists will attenuate fibrotic responses in normal and scleroderma skin fibroblasts by antagonizing intracellular profibrotic signaling pathways, and ameliorate scleroderma in mouse models. We will i) define ADP anti-fibrotic activity and mechanism of action in normal and scleroderma fibroblasts, 3D organotypic models and scleroderma skin biopsies; ii) develop novel ADP peptides; and iii) evaluate the two lead peptides in prevention, and promoting regression of, fibrosis in murine scleroderma. The mechanistic link between deregulated adipogenesis and fibrosis we propose here is conceptually innovative. The project is high impact since there are no approved treatments for scleroderma. Moreover, the results will have a strong impact on myriad fibrosing diseases that currently lack effective treatment.

PUBLIC HEALTH RELEVANCE: Scleroderma is a progressive chronic illness affecting multiple organs and often resulting in disability and death. Remarkably, there are no approved therapies to control scleroderma, and patients often have poor outcomes. The proposal seeks to identify novel mechanisms that are involved in the scarring process in the skin, and to develop novel treatment approaches to prevent and reverse the process. It is anticipated that successful accomplishment of our goals will lead to the validation of novel agents that could advance to clinical trials for the treatment of patients with scleroderma in the near future.