Evaluation of NCOA3 as a Transcriptional Co-regulator of Multiple Profibrotic Networks in Systemic Sclerosis

点击翻译按钮获取中文摘要

Systemic sclerosis (SSc) is a prototypical systemic fibrotic disease. Fibrotic tissue remodeling imposes a major burden on modern societies and has been estimated to contribute to at least 45% of deaths in the developed world. A major hallmark of SSc is the uncontrolled release of collagens and other components of the extracellular matrix by aberrantly activated fibroblasts. Differentiation of resting fibroblasts into myofibroblast is driven by a core set of profibrotic pathways that are shared across different diseases and organs, such as TGFβ and WNT signaling. Transcriptional co-regulators can synergistically interact with multiple transcription factors, thus enabling a broad-spectrum regulation of downstream signaling pathways. Our previous collaborative work provided evidence that the transcriptional coactivator NCOA3 is differentially expressed in SSc fibroblasts. Moreover, we provide evidence that NCOA3 regulates a network of profibrotic transcription factors including TGFβ/SMAD signaling and WNT/TCF signaling. Knockdown of NCOA3 prevented fibroblast activation and ameliorated skin fibrosis in mice. In the proposed project, we aim to further characterize the role of NCOA3 as a regulator of a profibrotic transcriptional network and evaluate its suitability as a target for antifibrotic therapies. We plan to: 1.) analyze the molecular mechanisms underlying the differential expression of NCOA3 in SSc; 2.) decipher the molecular mechanisms of the regulation of profibrotic transcription factors by NCOA3 using SMAD3 and TCF4 exemplarily; 3.) evaluate the translational therapeutic potential of NCOA3 using pharmacologic inhibition of NCOA3.