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.
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.
|Wei, Jun; Ghosh, Archit K; Chu, Haiyan et al. (2015) The Histone Deacetylase Sirtuin 1 Is Reduced in Systemic Sclerosis and Abrogates Fibrotic Responses by Targeting Transforming Growth Factor Î² Signaling. Arthritis Rheumatol 67:1323-34|
|Wei, Jun; Zhu, Hongyan; Komura, Kazuhiro et al. (2014) A synthetic PPAR-Ã½Ã½ agonist triterpenoid ameliorates experimental fibrosis: PPAR-Ã½Ã½-independent suppression of fibrotic responses. Ann Rheum Dis 73:446-54|
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|Fang, Feng; Ooka, Kohtaro; Bhattacharyya, Swati et al. (2011) The early growth response gene Egr2 (Alias Krox20) is a novel transcriptional target of transforming growth factor-Î² that is up-regulated in systemic sclerosis and mediates profibrotic responses. Am J Pathol 178:2077-90|
|Lam, Anna P; Flozak, Annette S; Russell, Susan et al. (2011) Nuclear Î²-catenin is increased in systemic sclerosis pulmonary fibrosis and promotes lung fibroblast migration and proliferation. Am J Respir Cell Mol Biol 45:915-22|
|Wei, Jun; Melichian, Denisa; Komura, Kazuhiro et al. (2011) Canonical Wnt signaling induces skin fibrosis and subcutaneous lipoatrophy: a novel mouse model for scleroderma? Arthritis Rheum 63:1707-17|
|Wei, Jun; Bhattacharyya, Swati; Tourtellotte, Warren G et al. (2011) Fibrosis in systemic sclerosis: emerging concepts and implications for targeted therapy. Autoimmun Rev 10:267-75|
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