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

酒精性肝病是美国酒精性脂肪性肝炎发病率和死亡率的常见原因， 疾病的早期阶段是可逆的，了解其分子发病机制对于 确定治疗这种疾病的新靶点。Wnt/β-catenin途径是一种细胞内信号转导途径 在正常肝脏发育、生长和再生中起重要作用的途径。的主要目的是 本研究旨在了解该通路在酒精性痴呆分子发病机制中的作用。 用小鼠酒精性肝病模型制作脂肪性肝炎。正在测试的中心假设是 蛋白β-连环蛋白是Wnt信号通路中的一个关键角色，在糖尿病的发生发展中起着保护作用。 酒精性脂肪性肝炎。为了验证这一假设，在特定目标1中，乙醇对Wnt/β-连环蛋白的影响 信号将在体外和体内确定。乙醇处理的原代肝细胞培养物，库普弗 细胞培养和肝癌细胞株将被用来研究Wnt信号在体外的变化。乙醇- FED小鼠将被用来研究Wnt信号在体内的变化。在具体目标2中，b-的损失的影响 用肝脏特异性b-连环蛋白基因敲除技术检测慢性酒精摄入对肝脏的连环蛋白 老鼠。肝组织学、肝损伤标志物、氧化应激、肝纤维化、细胞因子谱和改变 代谢基因的表达将在乙醇喂养的基因敲除小鼠的肝脏中得到表征。在……里面 特定目标3，酒精喂养对表达稳定、突变形式的转基因小鼠肝脏的影响 将对肝脏中b-连环蛋白的含量进行调查。这些研究将为分子事件提供新的见解 酒精性脂肪性肝炎的潜在发展。这项提议是为五年的职业生涯提供指导 发展奖和研究将在萨达山博士的主要指导下进行 蒙加在匹兹堡大学学习。该项目将为校长提供一个绝佳的机会 调查员Behari博士将发展成为酒精相关肝脏领域的独立调查员 疾病。

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 proposal 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 proposal 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.