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Consequences of AhR signaling during liver fibrosis

AhR 信号传导在肝纤维化过程中的后果

基本信息

批准号：
8898150
负责人：
KRISTEN Andrea MITCHELL
金额：
$ 22.37万
依托单位：
BOISE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8898150
关键词：
Address Affinity Applications Grants Aryl Hydrocarbon Receptor Biological Assay Biology Biomedical Research Carbon Tetrachloride Cause of Death Cells Centers of Research Excellence Collagen Type I DNA-Binding Proteins Development Dioxins Environment Environmental Pollution Extracellular Matrix Fibrosis Funding Future Gene Activation Gene Expression Gene Expression Profiling Genes Genome Goals Growth Factor Helix-Turn-Helix Motifs Hepatic Stellate Cell Hepatocyte Human In Vitro Inflammation Investigation Knockout Mice Ligands Ligation Link Liver Liver Cirrhosis Liver Fibrosis Liver diseases Measures Mediating Mentors Modeling Mus Myofibroblast Pharmaceutical Preparations Physiological Physiological Processes Process Receptor Activation Receptor Signaling Recovery Research Personnel Role Signal Pathway Signal Transduction System Technology Testing Tetrachlorodibenzodioxin Therapeutic Therapeutic Uses Toxic effect Transgenic Mice Variant Wild Type Mouse Work Wound Healing base bile duct chronic liver disease comparative cytokine design in vivo inhibitor/antagonist mouse model novel promoter research study response therapeutic target transcriptome sequencing

项目摘要

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.

慢性肝病和肝硬化是一个世界性的问题，在美国是第12大死亡原因。肝硬化之前是纤维化，这是一种可逆的伤口愈合反应，其特征在于肌成纤维细胞合成异常和过量的细胞外基质。肝肌成纤维细胞由异质前体细胞（最明显的是肝星状细胞）的分化产生。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，调节肌成纤维细胞分化的机制尚未完全了解，目前在美国还没有批准使用的抗纤维化药物。我们最近发现，肌成纤维细胞分化是通过外源性激活芳烃受体（AhR）增加的。我们将从机制上确定外源性和内源性AhR信号传导如何影响肌成纤维细胞分化和肝纤维化。我们将测试的假设，AhR信号是肌成纤维细胞分化的调节器。我们将确定AhR信号如何调节肌成纤维细胞分化。我们将测试的可能性，选择性AhR调节剂（SAhRM）持有的承诺，在治疗中使用全转录组测序和多重测定抑制肌成纤维细胞分化。我们将确定外源性AhR激活如何增强肌成纤维细胞分化使用良好的肝纤维化小鼠模型。我们将确定TCDD是否直接或间接靶向肝纤维化过程中的肌成纤维细胞分化，使用条件性AhR基因敲除小鼠，其中AhR从肝星状细胞或实质肝细胞中去除。作为矩阵生物学中COBRE的初级研究员，我将与我的科学导师一起完成目标，并为未来的R01资金制定赠款提案。