Role of Mechanosensitive Receptors During Biliary Proliferation and Fibrosis

描述（由申请人提供）： 在慢性胆汁淤积性肝病如原发性胆汁性肝硬化（PBC）和原发性硬化性胆管炎（PSC）的发病过程中，胆管细胞的生长和重塑对于维持胆汁质量和分泌功能至关重要。胆管细胞是胆管系统的上皮细胞，参与多种细胞过程。在胆汁淤积性肝脏疾病中，胆管细胞通过其细胞活化的产物，被认为是胆管损伤和上皮下纤维化之间的关键环节，上皮下纤维化是慢性肝胆损伤的特征。靶向对组织损伤引起的机械应力做出反应的特定因子可能有助于限制肝胆损伤和疾病（如PBC、PSC和肝纤维化）中发生的炎症和纤维化。新出现的证据表明，暴露于香烟烟雾可能会刺激慢性肝病向纤维化的进展，如PSC，PBC，慢性丙型肝炎和非酒精性脂肪性肝病。虽然机械应力，如胆管扩张（通常在PSC中观察到）和烟草使用（加速PBC患者的纤维化）激活胆管细胞，但导致这种表型的细胞和分子机制仍不清楚。β 7-烟碱乙酰胆碱受体（β 7-nAChR）介导尼古丁的增殖和纤维化作用，也可以被机械应力激活。我们提出了一个总体假设，即β 7-nAChR激活是介导促纤维化胆管细胞表型的关键和常见途径。这一假设将在三个特定目标中进行测试，这将确定（i）机械应力期间β 7-nAChR的配体依赖性激活是否通过增强miR-181和-200的表达诱导促纤维化表型;（ii）机械敏感性β 7-nAChR的激活是否刺激Ca 2+依赖性ACh分泌和miR-181和-200的表达;和（iii）抑制β 7-nAChR减弱胆汁淤积BDL小鼠体内活化的胆汁表型和纤维化。完成拟议的研究将提供一个框架，了解机械刺激如何触发局部和全身反应介导肝胆纤维化。这些发现可能会导致胆汁淤积的新治疗方法 肝脏疾病和降低美国退伍军人肝脏疾病的发病率和死亡率。

DESCRIPTION (provided by applicant): Cholangiocyte growth and remodeling are critical for the maintenance of biliary mass and secretory function during the pathogenesis of chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Cholangiocytes, the epithelia lining the biliary system, participate in a diverse array of cellular processes. In cholestatic livr diseases, cholangiocytes, through the products of their cellular activation, are implicated as the key link between bile duct injury and the subepithelial fibrosis that characterizes chronic hepatobiliary injury. Targeting specific factors that respond to the mechanical stress resulting from tissue injury may help limit inflammation and fibrosis that occur in hepatobiliary damages and diseases such as PBC, PSC and liver fibrosis. Emerging evidence indicates that exposure to cigarette smoke may stimulate the progression of chronic liver disease towards fibrosis such as PSC, PBC, chronic hepatitis C, and non-alcoholic fatty liver disease. Although mechanical stress such as occurs with biliary distention (commonly observed in PSC) and tobacco use (accelerates fibrosis in patients with PBC) activate cholangiocytes, the cellular and molecular mechanisms responsible for this phenotype remain unclear. The �7-nicotinic acetylcholine receptor (�7-nAChR) mediates the proliferative and fibrogenic effects of nicotine and can also be activated by mechanical stress. We propose the overall hypothesis that �7-nAChR activation is a key and common pathway responsible for mediating the profibrogenic cholangiocyte phenotype. This postulate will be tested in three Specific Aims, which will determine whether (i) ligand-dependent activation of �7-nAChR during mechanical stress induces a profibrogenic phenotype via enhanced expression of miR-181 and -200; (ii) activation of mechanosensitive �7-nAChR stimulates Ca2+-dependent ACh secretion and miR-181 and -200 expression; and (iii) inhibition of �7-nAChR attenuates the activated biliary phenotype and fibrosis in vivo in cholestatic BDL mice. Completion of proposed studies will provide a framework for understanding how mechanical stimuli trigger local and systemic responses mediate hepatobiliary fibrosis. The findings will likely lead to new therapeutic approaches for cholestatic liver diseases and a reduction of morbidity and mortality in American Veterans with liver diseases.