Role of Beta-Catenin in the Molecular Pathogenesis of Alcoholic Steatohepatitis

描述（由申请人提供）：酒精性肝病是美国发病率和死亡率的常见原因酒精性脂肪性肝炎，该疾病的早期阶段是可逆的，了解其分子发病机制对于确定该疾病的新治疗靶点至关重要。Wnt/ β -catenin通路是一种细胞内信号通路，在正常肝脏发育、生长和再生中起重要作用。本应用程序的主要目的是通过酒精性肝病小鼠模型了解该途径在酒精性脂肪性肝炎分子发病机制中的作用。正在验证的中心假设是蛋白质-连环蛋白，Wnt信号通路中的关键角色，在酒精性脂肪性肝炎的发展中起保护作用。为了验证这一假设，在特异性目标1中，乙醇对Wnt/ β -连环蛋白信号传导的影响将在体外和体内进行测定。乙醇处理的原代肝细胞培养，Kupffer细胞培养和肝癌细胞系将用于研究体外Wnt信号的变化。乙醇喂养小鼠将在体内研究Wnt信号的变化。在Specific Aim 2中，将使用肝脏特异性b-catenin敲除小鼠来确定慢性乙醇喂养中b-catenin损失对肝脏的影响。肝脏组织学、肝损伤标志物、氧化应激、肝纤维化、细胞因子谱和代谢基因表达的改变将在乙醇喂养的敲除小鼠的肝脏中被表征。在Specific Aim 3中，将研究乙醇喂养对肝脏中表达稳定的突变形式的b-连环蛋白的转基因小鼠的肝脏的影响。这些研究将为酒精性脂肪性肝炎发展的分子事件提供新的见解。该申请是一个为期五年的导师职业发展奖，研究将在匹兹堡大学的Satdarshan Monga博士的主要指导下进行。该项目将为首席研究员Behari博士提供一个绝佳的机会，使其发展成为酒精相关肝病领域的独立研究者。

DESCRIPTION (provided by applicant): Alcoholic liver disease is a common cause for morbidity and mortality in the U.S. Alcoholic steatohepatitis, the early phase of the disease, is reversible and understanding its molecular pathogenesis is essential to identify new therapeutic targets for this disease. The Wnt/beta-catenin pathway is an intracellular signaling pathway that plays an important role in normal liver development, growth, and regeneration. The main aim of this application is to understand the role of this pathway in the molecular pathogenesis of alcohol-induced steatohepatitis using mouse models of alcoholic liver disease. The central hypothesis being tested is that the protein beta-catenin, a key player in the Wnt signaling pathway, plays a protective role in the development of alcoholic steatohepatitis. To test this hypothesis, in Specific Aim 1, the effects of ethanol on Wnt/beta-catenin signaling will be determined both in vitro and in vivo. Ethanol-treated primary hepatocyte cultures, Kupffer cell cultures, and hepatoma cell lines will be used to investigate changes in Wnt signaling in vitro. Ethanol-fed mice will be utilized to study changes in Wnt signaling in vivo. In Specific Aim 2, the effects of loss of b-catenin on the liver with chronic ethanol feeding will be determined using liver-specific b-catenin knockout mice. Liver histology, markers of liver injury, oxidative stress, hepatic fibrosis, cytokine profile, and alterations in the expression of metabolic genes will be characterized in the livers of ethanol-fed knockout mice. In Specific Aim 3, the effect of ethanol feeding on the liver in transgenic mice expressing a stable, mutated-form of b-catenin in the liver will be investigated. These studies will provide new insights into the molecular events underlying development of alcoholic steatohepatitis. This application is for a five-year Mentored Career Development Award and the studies will be carried out under the primary mentorship of Dr. Satdarshan Monga at the University of Pittsburgh. The project will provide an outstanding opportunity to the principal investigator, Dr. Behari, to develop into an independent investigator in the area of alcohol-related liver disease.