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

项目摘要/摘要： 酒精性肝病是世界范围内一个主要的健康和经济问题。肝纤维化及其晚期形式， 肝硬变，几乎可以发生在所有类型的慢性肝病(CLD)中，包括酒精性肝损伤。 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变， 美国国立卫生研究院(NIH)报告称，肝硬变是导致疾病死亡的第12大原因 在美国。肝祖细胞(HPC)是另一种再生机制的来源，当 由于严重的肝损伤，肝细胞的增殖受到抑制。高性能计算与激活密切相关 肌成纤维细胞(Mf)与许多慢性肝病肝纤维化的严重程度相关。没有FDA批准的治疗方法 目前可用于任何纤维性疾病。迫切需要开发抗肝纤维化药物 在可逆期控制纤维化的进展。 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传递信号，包括 整合素。它是转录辅活化子是相关蛋白(YAP)的靶基因，起着 转化生长因子-β增强剂促进慢性肝纤维化及肝细胞活化 疾病。我们的研究证实了肝细胞核因子4α对结缔组织生长因子的微调调节 YAP和转化生长因子-β1信号在再生肝细胞中的拮抗作用 肝脏炎症、肝细胞增殖和胶原合成。Adamts7(去整合素和 具有凝血酶反应蛋白I型重复序列7的金属蛋白酶被鉴定为一种新的CTGF转换酶 在肝脏损伤期间。CTGF结合蛋白-细胞外基质蛋白(ECM)1-可抑制转化生长因子-β 激活，并显示出抗肝纤维化的潜力。CTGF在纤维化过程中的多方面调节提供 肝纤维化的诊断和随访以及耐人寻味的重要翻译机会 治疗干预的目标。利用我们最近开发的非侵入性成像技术，在AIM 1、探讨Adamts7在酒精性肝损伤中调节肝纤维化反应中的作用。 在目标2中，将评估ECM1对酒精性肝损伤和HPC激活的抗纤维化作用。 这项研究将为酒精性肝病的发病机制提供新的见解。我们所了解的知识 获得将有助于确定促进肝脏再生和减少肝纤维化的分子靶点。

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.