Scleroderma (Systemic Sclerosis, SSc) is a devastating multiorgan disease with a prevalence of approximately 250 cases per million people in the US. The hallmark features of SSc include fibroproliferative vasculopathy, immune dysfunction, and extensive skin and organ fibrosis. Despite extensive clinical and pathological findings concerning vascular dysfunction, the mechanism underlying vascular disease and the relationship between vasculopathy and other disease manifestations is poorly understood. The progress in this area is hampered by the heterogeneity of the disease and the lack of the animal models that adequately represent the complex nature of SSc. Based on extensive studies that implicated deficiency of transcription factor Fli1 in SSc vasculopathy and fibrosis, we have established a transgenic model of SSc that recapitulates many of the vascular features of SSc and shows evidence of increased susceptibility to fibrosis. In addition, we developed an inducible model of dermal fibrosis based on Angiotensin II infusion that is characterized by vascular injury, inflammation and fibrosis, thus recapitulating the principal features of SSc. The proposed studies will test the hypothesis that persistent endothelial cell injury, in part mediated through activation of the TLR4/PKC?/Fli1 pathway, is a key pathogenic event that leads to myofibroblast activation and fibrosis in SSc. The studies will include investigation of the molecular mechanisms of LPS/TLR4 induced endothelial-mesenchymal transition (EndMT), with the emphasis on the PKC?-Fli1 axis combined with the comprehensive analyses of the new SSc mouse models. To further substantiate the pathological role of the PKC?/Fli1 pathway we will determine whether blockade of this pathway is therapeutically effective in reducing vasculopathy and fibrosis in animal models of SSc. We propose the following specific aims: 1: To determine the molecular mechanism of LPS/TLR4-induced activation of endothelial cells focusing on the role of PKC?/Fli1 as mediators of this process. 2: To elucidate the relationship between vasculopathy and fibrosis using mouse models of SSc. 3: To determine the therapeutic potential of novel PKC? inhibitors in reducing vasculopathy and fibrosis in vivo.
We have successfully established experimental models of SSc recapitulating the key disease features, including vasculopathy and fibrosis that will allow us to begin to address some of the unanswered questions related to the pathogenesis of SSc and characterize candidate molecules and pathways in SSc. The new knowledge generated by these studies will help to unravel the molecular basis of the vascular injury and the relationship between vasculopathy and fibrosis and ultimately provide logical and effective targets for therapeutic intervention in SSc.
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