Adipokine Modulation of Fibrosis: Novel Scleroderma Pathway

Project: Research project

Project Details

Description

The pathogenesis of fibrosis in systemic sclerosis (SSc) is poorly understood and effective treatments are lacking. Recent findings point to a previously unappreciated complex relationship between subcutaneous adipose tissue (SAT), adipogenesis and fibrogenesis in SSc. SAT is an important reservoir of both multipotent mesenchymal progenitor cells, and adipocytes secreting adipokines with pro- and anti-fibrotic paracrine activities. Loss of SAT is associated with dermal fibrosis in SSc and precedes dermal fibrosis in mouse models of scleroderma, suggesting that it is a primary event in pathogenesis. In response to the adipogenic master regulator PPAR-gamma, SAT secretes copious amounts of adiponectin. Our preliminary results showed reduced levels of adiponectin in the serum and skin in SSc, and an inverse correlation with skin score. Adiponectin has potent anti-fibrotic effects, and mediates the salutary effects of PPAR-gamma in fibroblasts, whereas loss of adiponectin in the mouse results in exacerbated fibrosis. I hypothesize that impaired adiponectin function results in persistent hypoadiponectinemic state in SSc that contributes to unchecked fibroblast activation and progression of skin fibrosis. Further, I hypothesize that adiponectin is a novel fibrosis biomarker and a potential target for therapy. In this proposal I will i) examine how adiponectin gain-of-function modulates experimental fibrosis in transgenic mice; and ii) evaluate the clinical correlates of serum and tissue adiponectin levels in well-characterized SSc patient cohorts. These results will contribute to a better understanding of fibrosis, and indicate if augmenting adiponectin in specific SSc patient subsets, may be a potential approach to therapy.
StatusFinished
Effective start/end date1/1/1512/31/18

Funding

  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (5R03AR066343-03 REVISED)

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