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

系统性硬化症（SSc）是一种典型的系统性纤维化疾病。纤维化组织重塑给现代社会造成了重大负担，据估计，发达国家至少45%的死亡是由纤维化组织重塑造成的。SSc的一个主要特征是异常激活的成纤维细胞不受控制地释放胶原和细胞外基质的其他成分。静息成纤维细胞向肌成纤维细胞的分化是由一系列核心的促纤维化通路驱动的，这些通路在不同的疾病和器官中共享，如TGFβ和WNT信号。转录共调节因子可以与多种转录因子协同作用，从而实现对下游信号通路的广谱调节。我们之前的合作工作提供了证据，证明转录共激活因子NCOA3在SSc成纤维细胞中存在差异表达。此外，我们提供的证据表明，NCOA3调节了包括TGFβ/SMAD信号和WNT/TCF信号在内的促纤维化转录因子网络。敲低NCOA3可阻止成纤维细胞活化，改善小鼠皮肤纤维化。在拟议的项目中，我们的目标是进一步表征NCOA3作为促纤维化转录网络调节剂的作用，并评估其作为抗纤维化治疗靶点的适用性。我们计划：1)分析NCOA3在SSc中差异表达的分子机制；2.)以SMAD3和TCF4为例，揭示NCOA3调控促纤维化转录因子的分子机制；3)通过药理抑制NCOA3来评估NCOA3的转化治疗潜力。

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.