Consequences of AhR signaling during liver fibrosis

慢性肝病和肝硬变是一个世界性的问题，在美国排名第12位的死亡原因是肝纤维化。肝纤维化是一种可逆的创面愈合反应，其特征是肌成纤维细胞合成异常和过度的细胞外基质。肝肌成纤维细胞起源于异种前体细胞的分化，尤其是肝星状细胞。靶向肌成纤维细胞分化是限制纤维化和促进肝病恢复的合理策略。然而，调控肌成纤维细胞分化的机制尚不完全清楚，目前美国还没有批准使用的抗纤维化药物。我们最近发现，肌肉成纤维细胞的分化是通过外源性激活芳香烃受体(AhR)来促进的。我们将从机制上确定外源性和内源性AhR信号如何影响肌成纤维细胞分化和肝纤维化。我们将验证AhR信号是肌成纤维细胞分化调节因子的假设。我们将确定AhR信号如何调节肌成纤维细胞分化。我们将通过整个转录组测序和多重分析来测试选择性AhR调节剂(SAhRM)在抑制肌成纤维细胞分化方面具有治疗作用的可能性。我们将使用成熟的小鼠肝纤维化模型来确定外源性AhR激活如何促进肌成纤维细胞分化。我们将使用从肝星状细胞或实质肝细胞中去除AhR的条件性AhR基因敲除小鼠，确定TCDD是否直接或间接地针对肝纤维化期间的肌成纤维细胞分化。作为矩阵生物学科布雷的初级研究员，我将与我的科学导师合作，完成这些目标，并为未来的R01资金制定一项赠款提案。

Chronic liver disease and cirrhosis are a worldwide problem and the 12th leading cause of death in the U.S. Liver cirrhosis is preceded by fibrosis, which is a reversible, wound-healing response characterized by the synthesis of abnormal and excessive extracellular matrix by myofibroblasts. Liver myofibroblasts arise from the differentiation of heterogenous precursors, most notably hepatic stellate cells. Targeting myofibroblast differentiation is a logical strategy to limit fibrosis and enhance recovery from liver disease. However, the mechanisms that regulate myofibroblast differentiation are not completely understood, and currently there are no anti-fibrotic drugs approved for use in the U.S. We recently discovered that myofibroblast differentiation is increased by exogenous activation ofthe aryl hydrocarbon receptor (AhR). We will mechanistically determine how exogenous and endogenous AhR signaling impacts myofibroblast differentiation and liver fibrosis. We will test the hypothesis that AhR signaling is a regulator of myofibroblast differentiation. We will determine how AhR signaling regulates myofibroblast differentiation. We will test the possibility that a selective AhR modulator (SAhRM) holds promise for therapeutic use in suppressing myofibroblast differentiation using whole transcriptome sequencing and multiplex assays. We will determine how exogenous AhR activation enhances myofibroblast differentiation using well-established mouse models of liver fibrosis. We will determine if TCDD directly or indirectly targets myofibroblast differentiation during liver fibrosis using conditional AhR knockout mice in which the AhR is removed from either hepatic stellate cells or from parenchymal hepatocytes. As Junior Investigator in the COBRE in Matrix Biology, I will work with my scientific mentor to complete the aims and develop a grant proposal for future R01 funding.