Matricellular Signaling in Hepatobiliary Injury Repair

 描述(申请人提供)：肝纤维化是一种细胞外基质的过度积聚，作为一种对各种肝脏疾病的慢性损伤的愈合反应，而不考虑潜在的病因。晚期肝纤维化可能导致肝硬变、肝功能衰竭和肿瘤。细胞外基质沉积通过促进组织形成和完整性对伤口愈合至关重要，但在慢性损伤中通常变得不受控制，并导致纤维化。胆管反应是肝脏损伤反应的一部分，发生在实质和门静脉间隔的间期，促进胆管再生。尽管胆管反应在胆汁和胆汁淤积损害中表现突出，但在几乎所有慢性人类肝病中都能观察到胆管反应。最近的研究表明，基质细胞蛋白CCN1通过整合素v5介导的NFB活化，诱导胆管细胞增殖和胆管反应，从而导致Jag1表达和Jag1/Notch信号转导。此外，CCN1还能抑制和消除肝毒素(四氯化碳)或胆汁淤积症(胆管结扎)b诱导的肝星状细胞和门静脉成纤维细胞的细胞衰老所致的肝纤维化。CCN1似乎还调节肌成纤维细胞的激活和炎症的消退。基于这些观察，我们假设CCN1通过结合不同细胞类型中不同的整合素，在肝胆损伤修复的不同阶段发挥多种功能。我们将从三个具体的目标来审视这一假说：(1)对迄今未发现的胆管反应中的CCN1-v5-NFB轴进行遗传学和功能分析；(2)研究CCN1如何诱导胆管反应龛中的反应性胆管细胞表型和肝祖细胞的分化；以及(3)研究CCN1如何调控损伤修复过程中纤维化形成的开始和终止。这些研究将阐明CCN1作为慢性肝病损伤修复的关键调节因子的不同作用，并可能导致预防和治疗肝纤维化的新的治疗靶点和治疗策略。

 DESCRIPTION (provided by applicant): Liver fibrosis is the excessive accumulation of extracellular matrix as a wound healing response to chronic injuries from a broad range of liver diseases, irrespective of the underlying etiology. Advanced liver fibrosis may lead to cirrhosis, liver failure, and neoplasia. Extracellular matrix deposition is crucial to wound healing by promoting tissue formation and integrity, but commonly becomes uncontrolled in chronic injuries and leads to fibrosis. Ductular reaction is part of the injury response in the liver occurring at te interphase of the parenchymal and portal compartments that promotes bile duct regeneration. Although prominent in response to biliary and cholestatic damages, ductular reaction is observed in virtually all chronic human liver diseases. Recent studies have revealed that the matricellular protein CCN1 induces cholangiocyte proliferation and ductular reaction in response to cholestatic injuries through integrin v5-mediated activation of NFB, leading to Jag1 expression and Jag1/Notch signaling. Furthermore, CCN1 is able to restrict and resolve liver fibrosis induced by either hepatotoxin (carbon tetrachloride) or cholestasis (bile duct ligation) b inducing cellular senescence in myofibroblasts derived from hepatic stellate cells and portal fibroblasts. CCN1 also appears to regulate myofibroblast activation and resolution of inflammation. Based on these observations, we hypothesize that CCN1 serves multiple functions in different stages of hepatobiliary injury repair through binding distinct integrins in different cell types. We will scrutinize this hypothesis in three specific aims: (1) to conduct genetic and functional analyses of the heretofore unexplored CCN1-v5-NFB axis in ductular reaction; (2) to examine how CCN1 induces the reactive cholangiocyte phenotype and differentiation of hepatic progenitor cells in the ductular reaction niche; and (3) to investigate how CCN1 regulates the initiation and termination of fibrogenesis in injury repair. These studies will elucidate the diverse roles of CCN1 as a critical regulator of injury repair in chronic liver diseases, and may lead to new therapeutic targets and treatment strategies for the prevention and treatment of liver fibrosis.