Genesis and consequences of inborn and acquired alterations of hepatocellular keratin architecture

角蛋白8和角蛋白18(K8/K18)是消化上皮细胞的主要中间丝蛋白。成人肝细胞是独特的，因为它们只表达K8/K18，而其他类型的细胞表现出更复杂的角蛋白表达模式。相应地，K8/K18改变导致了主要的肝脏表型。例如，K8/K18变异使小鼠容易受到肝脏损伤，并使人类更容易发生和发展肝病。K8/K18网络重组为聚集体，称为Mallory-Denk小体(MDB)，是包括酒精性和非酒精性脂肪性肝炎在内的各种肝脏疾病的特征。我们建议研究肝细胞K8/K18结构的先天和后天改变，以确定K8/K18结构紊乱的分子后果，并确定受K8/K18变异特别影响的背景。角蛋白结构改变的功能含义将在细胞水平和表达两种最常见的人类K8/K18变体的转基因小鼠中进行研究。分析将在基本条件下进行，并在与疾病相关的压力模型中进行。角蛋白重组成MDB的机制将在喂食MDB诱导剂3，5-二乙氧基甲酰-1，4-二氢氯仿的小鼠身上进行评估。人类关联研究和人体活检标本检查将补充啮齿动物数据。我们的研究将加强对K8/K18细胞骨架在肝脏疾病中作用的理解，并将导致新的治疗方法。

Keratins 8 and 18 (K8/K18) are the major intermediate filament proteins of digestive epithelia. Adult hepatocytes are unique in that they express K8/K18 exclusively, whereas other cell types exhibit a more complex keratin expression pattern. Accordingly, K8/K18 alterations result in a predominant liver phenotype. For example, K8/K18 variants render mice susceptible to hepatic injury and predispose humans to liver disease development and progression. K8/K18 network reorganization into aggregates termed Mallory-Denk bodies (MDBs) is characteristic of various liver disorders including alcoholic and non-alcoholic steatohepatitis. We propose to study inborn and acquired alterations of hepatocellular K8/K18 architecture to define the molecular consequences of K8/K18 disorganization and to identify contexts that are particularly impacted by K8/K18 variants. The functional implications of altered keratin architecture will be examined at the cellular level and in transgenic mice expressing the two most common human K8/K18 variants. Analyses will be performed under basal conditions and in disease-relevant stress models. The mechanisms underlying keratin reorganization into MDBs will be evaluated in mice fed 3,5-diethoxycarbonyl-1,4-dihydrocollidine, an established MDB inducer. Human association studies and examination of human biopsy specimen will complement the rodent data. Our studies will enhance the understanding of the role of the K8/K18 cytoskeleton in liver disease and should lead to novel therapeutic approaches.