Fibroblast TGF-beta/Signaling in Scleroderma: Modulation by PPAR-gamma

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DESCRIPTION (provided by applicant): Systemic sclerosis (SSc) is a devastating condition with no disease-modifying treatment. Fibrosis, the hallmark of SSc, is caused by fibroblast activation with collagen overproduction and myofibroblast differentiation. Transforming growth factor-b (TGF-b) is a potent inducer of fibroblast activation, and plays a key role in the pathogenesis of SSc. TGF-b responses are mediated through intracellular Smad pathways and p300, a transcriptional coactivator and histone acetyltransferase. Recently, we found that peroxisome proliferator-activated receptor (PPAR)-3 is expressed in normal fibroblasts. PPAR-g is a nuclear receptor with key roles in adipogenesis and insulin sensitivity. Ligands for PPAR-g are in clinical use to treat type 2 diabetes. We showed that PPAR-g ligands abrogated collagen gene expression induced by TGF-b, indicating an important novel biological activity of PPAR-g. We also demonstrated that expression of PPAR-g protein and mRNA was reduced in some patients with SSc. We hypothesize that PPAR-g is an endogenous suppressor of fibrotic responses, and impaired expression or activity could be a factor in progressive fibrosis in SSc; thus PPAR-g may be a novel target for anti-fibrotic therapy. We will explore the anti-fibrotic role of PPAR-g and its mechanism in vitro and in vivo. In Specific Aim 1, we will characterize the anti-TGF-b mechanisms of action of PPAR-g in mouse and human cells with defective endogenous PPAR-g, and examine the modulation of TGF-b signaling by PPAR-g. In Specific Aim 2 we will examine the role of p300 in mediating TGF-b responses and in the antagonistic cross-talk with PPAR-g. In Specific Aim 3 we will examine the effect of PPAR-g ligands in mouse models of scleroderma, and study the fibrotic response in a novel transgenic mouse with fibroblast-specific conditional deletion of PPAR-g. In Specific Aim 4, we will examine the expression, activity and clinical correlates of PPAR-g in SSc. These studies will deepen our understanding of aberrant fibroblast activation in SSc, and provide the first insight into the role of PPAR-g in the process. The proposed research will accelerate the development of novel anti-fibrotic treatments for SSc and other fibrosing diseases. PUBLIC HEALTH RELEVANCE: Systemic sclerosis is an orphan disease with poorly understood pathogenesis and no disease-modifying treatment. Anti-fibrotic therapy could improve survival and quality of life in SSc as well as other fibrosing conditions. Recent studies indicate that PPAR-g is a potent negative regulator of fibrotic responses and may represent a novel target for therapy. Currently, nothing is known regarding the regulation and role of PPAR-g in SSc. The proposed studies will provide a better definition of fibrosis in SSc, the role of PPAR-g in regulating the response, and the potential clinical utility of therapies targeting PPAR-g in SSc.