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

肝细胞角蛋白结构先天性和后天性改变的起源和后果

基本信息

批准号：
120427175
负责人：
Professor Dr. Pavel Strnad
金额：
--
依托单位：
Klinik für Gastroenterologie, Stoffwechselerkrankungen und Internistische Intensivmedizin (Med. Klinik III)
依托单位国家：
德国
项目类别：
Independent Junior Research Groups
财政年份：
2009
资助国家：
德国
起止时间：
2008-12-31 至 2013-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/120427175?language=en
关键词：
Genesis consequences inborn acquired alterations

项目摘要

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.

角蛋白8和18（K8/K18）是消化道上皮细胞的主要中间丝蛋白。成体肝细胞的独特之处在于它们仅表达K8/K18，而其他细胞类型表现出更复杂的角蛋白表达模式。因此，K8/K18改变导致主要的肝脏表型。例如，K8/K18变体使小鼠易受肝损伤，并使人类易患肝病发展和进展。K8/K18网络重组成称为Mallory-Denk小体（MDB）的聚集体是各种肝脏疾病的特征，包括酒精性和非酒精性脂肪性肝炎。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紊乱的分子后果，并确定特别受K8/K18变体影响的背景。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检查改变的角蛋白结构的功能意义。将在基础条件下和疾病相关应激模型中进行分析。将在喂食3，5-二乙氧羰基-1，4-二氢可力丁（一种已确定的MDB诱导剂）的小鼠中评价角蛋白重组为MDB的潜在机制。人类关联研究和人类活检标本的检查将补充啮齿动物数据。我们的研究将增强对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。