Oxidant Stress and Fibrosis in Alcoholic Liver Injury

描述（由申请人提供）：酒精性肝病仍然是一种高度流行且往往致命的酒精滥用并发症，其病因尚不完全清楚。了解酒精性肝病的基础可以改善数百万受此问题困扰的美国人的健康。这个探索性酒精研究中心的总体目标是阐明酒精性肝损伤和纤维化的发病机制，由于氧化应激，通过纳入新的疾病模型，并促进独特的协同作用之间的各种研究人员具有互补的利益和优势。这将推动我们致力于发展酒精研究中心（P50）。具体而言，我们将：1）通过研究氧化应激、细胞-细胞相互作用和新型转录调节因子KLF 6在介导肝损伤和纤维化中的作用，阐明酒精性肝病的机制基础; 2）通过使用斑马鱼、工程化的哺乳动物细胞系，3）在西奈山医学院的研究人员之间建立新的协同作用，以创造新的方法来理解酒精性肝损伤和纤维化; 4）通过利用现有的NIH资助的培训计划，并通过建立与酒精性肝病相关主题的年度研讨会和定期研讨会，创造新的教育和培训机会来研究酒精性肝损伤和纤维化。为了实现这些目标，该中心将包括一个行政核心和两个研究核心。（一个包括哺乳动物和斑马鱼试剂和动物模型的模型核心;以及一个由经验丰富的肝脏病理学家领导的形态学核心）;两个探索性项目：a）肝损伤、纤维化和KLF 6基因对氧化应激的选择性剪接; B）斑马鱼作为酒精性肝病的模型;三个试点可行性项目：a）酒精介导的肝损伤对生长激素生物学的影响; B）Cdc 37-酒精诱导的肝细胞癌的早期生物标志物和HspQO抑制剂作为治疗剂的作用; c）酒精对小鼠和人胚胎干细胞衍生的成肝细胞的影响。总的来说，该项目的高度协作性有望使用新模型和最先进的方法对酒精性肝损伤的分子基础产生重要的新见解。

DESCRIPTION (provided by applicant): Alcoholic liver disease remains a highly prevalent and often lethal complication of alcohol abuse, whose etiology is incompletely understood. Understanding the basis of alcoholic liver disease could improve the health of millions of Americans afflicted by this problem. The overall objective of this exploratory alcohol research center is to elucidate the pathogenesis of alcoholic liver injury and fibrosis due to oxidant stress by incorporating novel models of disease and promoting unique synergistic interactions among a diverse range of investigators with complementary interests and strengths. This will advance our commitment to developing an Alcohol Research Center (P50). Specifically, we will: 1) Elucidate the mechanistic underpinnings of alcoholic liver disease by studying the roles of oxidant stress, cell-cell interactions and a novel transcriptional regulator, KLF6, in mediating liver injury and fibrogenesis; 2) Define novel models of alcoholic liver injury, non-alcoholic steatohepatitis (NASH) and fibrosis through the use of zebrafish, engineered mammalian cell lines, and transgenic models of alcohol-induced liver injury in mice; 3) Forge new, synergistic interactions among investigators at the Mount Sinai School of Medicine to create novel approaches to understanding alcoholic liver injury and fibrosis; 4) Create new educational and training opportunities to study alcoholic liver injury and fibrosis by leveraging existing NIH-funded training programs, and by establishing annual symposia and regular seminars in topics related to alcoholic liver disease. To address these aims, the Center will include an Administrative and two Research Cores (a Models Core that will include both mammalian and zebrafish reagents and animal models; and a Morphology Core led by a highly experienced hepatopathologist); Two Exploratory Projects: a) Hepatic injury, fibrosis and alternative splicing of the KLF6 gene in response to oxidant stress; b) zebrafish as a model for alcoholic liver disease; Three Pilot Feasibility Projects; a) Effects of alcohol-mediated liver injury on growth hormone biology; b) Cdc37 an early biomarker of alcohol induced hepatocellular carcinoma and the role HspQO inhibitors as therapeutic agents; c) Effect of alcohol on mouse and human embryonic stem cell-derived hepatoblasts. Collectively, the highly collaborative nature of the program promises to yield important new insights into the molecular basis of alcoholic liver injury using novel models and state-of-the-art methods.