Matricellular Signaling in Hepatobiliary Injury Repair

 描述（由申请人提供）：肝纤维化是细胞外基质的过度积累，作为对广泛肝病慢性损伤的伤口愈合反应，与潜在病因无关。晚期肝纤维化可能导致肝硬化、肝衰竭和肿瘤。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室的间期，促进胆管再生。尽管胆管反应对胆道和胆汁淤积性损伤的反应突出，但在几乎所有慢性人类肝病中均观察到胆管反应。最近的研究表明，基质细胞蛋白CCN 1诱导胆管细胞增殖和胆管反应，以响应胆汁淤积性损伤，通过整合素α v β 5介导的NF κ B B活化，导致Jag 1表达和Jag 1/Notch信号传导。此外，CCN 1能够限制和解决由肝毒素（四氯化碳）或胆汁淤积（胆管结扎）诱导的肝纤维化B诱导源自肝星状细胞和门静脉成纤维细胞的肌成纤维细胞的细胞衰老。CCN 1似乎还调节肌成纤维细胞活化和炎症的消退。基于这些观察，我们假设CCN 1通过结合不同细胞类型中的不同整合素在肝胆损伤修复的不同阶段发挥多种功能。我们将在三个具体目标中仔细研究这一假说：（1）对迄今为止尚未探索的胆管反应中的CCN 1-β v β 5-NF β B轴进行遗传和功能分析;（2）检查CCN 1如何诱导反应性胆管细胞表型和胆管反应龛中肝祖细胞的分化;（3）研究CCN 1如何调节损伤修复中纤维化的起始和终止。这些研究将阐明CCN 1作为慢性肝病损伤修复的关键调节因子的多种作用，并可能为预防和治疗肝纤维化带来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.