The role of PARP1 in the pathogenesis of fibrotic disorders

• Applicant: Dr. Clara Dees
• Subject Area: Rheumatology
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 271929393

Systemic sclerosis (SSc) is a chronic fibrotic autoimmune disease with unknown etiology, which affects the skin and several internal organs. The most obvious histopathological hallmark of SSc is an aberrant accumulation of extracellular matrix proteins synthesized and released by activated fibroblasts, which destroys the physiological tissue architecture and impairs the function of the affected organs. The mechanisms leading to the chronic activation of fibroblasts are only partially understood to date. Therefore, the present project aims to analyze the role of PARP1 in fibroblast activation and fibrogenesis. Deregulation of PARP proteins has already been implicated in several human diseases like tumors, cardiovascular and neurological disorders as well as organ fibrosis such as lung or kidney fibrosis, suggesting that this protein family may be also of interest for research in SSc and skin fibrosis. The expression of PARP1 is strongly downregulated in cultured fibroblasts and in the skin of SSc patients, which can also be induced by TGFbeta, an accepted key-player in fibrogenesis. Consistently, blockade of PARP1 in vivo potently aggravates bleomycin-induced dermal fibrosis. In addition, knockout of PARP1 exacerbates the activation of the TGFbeta-Smad signalling cascade.Using both pharmacological and genetic approaches, this project aims to characterize the role of PARP1 in skin fibrosis in vitro and in different animal models in vivo. In addition, the mechanism by which PARP1 is repressed in SSc patients and by TGFbeta will be evaluated. In order to evaluate whether the repression of PARP1 is caused by epigenetic mechanisms like DNA hypermethylation and histone deacetylation, selective antagonists of histone deacetylases and DNA methyltransferases as well as siRNA-mediated knockdown and expression vectors will be employed.

• DFG Programme: Research Grants