Regulation of the pro-fibrotic connective tissue growth factor in alcoholic liver disease: mechanisms and targeting approaches

项目概要/摘要： 酒精性肝病是全球范围内的一个主要健康和经济问题。肝纤维化及其晚期形式， 肝硬化，可以发生在几乎所有类型的慢性肝病（CLD），包括酒精诱导的肝损伤。 根据美国肝脏基金会的数据，目前有550万美国人患有慢性肝病或肝硬化， 美国国立卫生研究院（NIH）报告肝硬化是第12大疾病死亡原因 在美国肝祖细胞（HPC）是替代再生机制的来源， 肝细胞增殖由于严重的肝损伤而受到抑制。HPC与激活的 肌成纤维细胞（MF），并与许多CLD中的肝纤维化严重程度相关。没有FDA批准的治疗 目前可用于任何纤维化疾病。抗肝纤维化药物的开发迫在眉睫 在可逆阶段控制纤维化的进展。 结缔组织生长因子（CTGF）是一种促纤维化介质，调节细胞-细胞和细胞-基质 通过与多种生长因子、基质蛋白和细胞表面蛋白结合来进行信号传导，包括 整合素它是转录辅激活因子Yes相关蛋白（雅普）的靶基因，并作为一个转录因子， 转化生长因子-β增强剂，促进慢性肝纤维化和HPC活化 疾病我们的研究表明Ctgf通过肝细胞核因子（hepatocyte nuclear factor，Hnf）4α进行微调调节 再生肝细胞中雅普和TGF-β1信号传导的拮抗作用，而Ctgf缺乏降低了 肝脏炎症、肝细胞增殖和胶原合成。Adamts 7（一种去整合素， 具有血小板反应蛋白I型重复序列的金属蛋白酶7）被鉴定为Ctgf周转的新酶 肝损伤时。Ctgf结合蛋白-细胞外基质蛋白（ECM）1-被鉴定为抑制TGF-β 活化并表现出抗纤维化潜力。纤维化过程中Ctgf的多方面调节提供了 肝纤维化的诊断和随访的重要转化机会， 治疗干预的目标。利用我们最近开发的一种非侵入性成像技术， 1，将检查Adamts 7在酒精诱导的肝损伤期间调节纤维化反应的功能。 在目标2中，将评估ECM 1对酒精性肝损伤和HPC活化的抗纤维化作用。 这项研究将为酒精性肝病提供新的机制见解。我们的知识 获得将有助于确定分子靶点，以增强肝再生和减少肝纤维化。

Project Summary / Abstract: Alcoholic liver disease is a major health and financial concern worldwide. Liver fibrosis and its advanced form, cirrhosis, can occur in virtually all types of chronic liver disease (CLD) including alcohol-induced liver injury. According to the American Liver Foundation, 5.5 million Americans are currently afflicted with CLD or cirrhosis, and the National Institutes of Health (NIH) reports cirrhosis as the 12th leading cause of death due to disease in America. Hepatic progenitor cells (HPCs) are the source of an alternative regenerative mechanism when hepatocyte proliferation is inhibited due to severe liver damage. HPC are closely associated with activated myofibroblast cells (MF) and correlate with severity of liver fibrosis in many CLD. No FDA approved treatment is currently available for any fibrotic disorder. There is an urgent need for the development of anti-fibrotic drugs to control progression of fibrosis while in reversible stages. Connective tissue growth factor (Ctgf) is a profibrotic mediator and modulates cell-cell and cell-matrix signaling through binding to a variety of growth factors, matrix protein, and cell surface proteins including integrins. It is a target gene of the transcriptional coactivator Yes-associated protein (Yap) and acts as an enhancer of transforming growth factor (Tgf)-β, promoting liver fibrosis and HPC activation in chronic liver disease. Our studies demonstrated fine-tuned regulation of Ctgf via hepatocyte nuclear factor (Hnf)4α antagonism of Yap and TGF-β1 signaling in regenerating hepatocytes whereas Ctgf deficiency reduces hepatic inflammation, hepatocyte proliferation and collagen synthesis. Adamts7 (a disintegrin and metalloproteinase with thrombospondin type I repeat 7) was identified as a novel enzyme for Ctgf turnover during liver injury. The Ctgf binding protein-extracellular matrix protein (ECM)1- was identified to inhibit Tgf-β activation and exhibited anti-fibrotic potential. The multifaceted regulations of Ctgf during fibrosis offers important translational opportunities for diagnosis and follow-up of hepatic fibrogenesis as well as intriguing targets for therapeutic interventions. Utilizing a noninvasive imaging technique we recently developed, in Aim 1, the function of Adamts7 in regulating fibrotic responses during alcohol-induced liver injury will be examined. In Aim 2, the anti-fibrotic effects of ECM1 on alcoholic liver injury and HPC activation will be assessed. This study will provide new mechanistic insights during alcoholic liver disease. The knowledge we obtain will help identify molecular targets to enhance liver regeneration and reduce liver fibrosis.