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 intradermal adipose tissue (IAT) and fibrosis in SSc. Adipocytes are not simply a storage reservoir of fat, it critically control metabolism as an endocrine organ by secreting adipokines. Adiponectin is the most abundant adipose-specific adipokine with anti-fibrotic activities. Loss of IAT is associated with dermal fibrosis in SSc and precedes the onset of dermal fibrosis in mouse models of scleroderma, suggesting that it is a primary event in pathogenesis. Our preliminary results showed reduced levels of adiponectin in the serum and skin in SSc, and an inverse correlation with extent of skin fibrosis. Adiponectin has potent anti-fibrotic effects, and loss of adiponectin in the mouse results in exacerbated fibrosis. I hypothesize that loss of IAT results in persistent reduced levels of adiponectin in SSc that contributes to fibroblast activation and progression of skin fibrosis. In this proposal I will i) elucidate the mechanisms by which adiponectin is permissive to skin fibrosis in animal models of scleroderma; and ii) determine the effects of adiponectin agonists in organ fibrosis as potential novel therapeutic strategy. These results will contribute to a better understanding of fibrosis, and indicate if augmenting adiponectin may be a potential approach to therapy in SSc.
|Effective start/end date||4/1/16 → 3/31/19|
- Scleroderma Foundation (Agreement 2/20/16)