Modulators of hepatic response to TGF-ß mediated cellular injury in inbred mice: Identification of modifiers of fibrosis susceptibility

近交小鼠肝脏对 TGF-α 介导的细胞损伤反应的调节剂：纤维化易感性调节剂的鉴定

• 批准号: 135720730
• 负责人: Professor Dr. Frank Lammert
• 金额: --
• 依托单位: II. Medizinische Klinik: Gastroenterologie, Hepatologie, Infektiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 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/135720730?language=en
• 关键词: Modulators; hepatic; response; TGF; mediated

Hepatic fibrosis is a non-specific response to chronic liver injury, the two most common causes being viral hepatitis or alcohol abuse. Twin studies and ethnic differences indicate that genetic factors play a role in predisposition to and progression of both types. In contrast to viral hepatitis, no firm associations between genetic variants and susceptibility to alcoholic liver fibrosis have been identified to date. Transforming growth factor (TGF)-β is considered the master pro-fibrogenic cytokine, driving fibrosis in response to various modes of injury. This central role makes every modifier locus of the response to TGF-β mediated hepatic injury a candidate gene for fibrosis susceptibility. The aim of this project is to identify the modifier genes of TGF-β mediated injury, using hepatocytes isolated from genetically distinct inbred mouse strains. Hepatocytes are highly responsive to TGF-β. Their demise leads to activation of Kupffer cells and subsequent release of inflammatory cytokines as well as activation of hepatic stellate cells with enhanced expression of growth factors and extracellular matrix components. Here, we propose to avail of a genetic reference population generated from progeny of inbred mouse lines C57BL/6J and DBA/2J, also known as BXD recombinant inbred lines. The genetically distinct hepatocytes from these mouse lines will be challenged with TGF-β, and phenotypic differences (cellular damage, gene expression) will be quantified to delineate differences in response. Quantitative trait locus mapping, i.e. linkage analysis in the BXD panel, will enable us to identify the genetic loci that underlie differential responses to TGF-β by allelic variation. This experimental framework will allow us to assess the orthologous human regions and candidate genes for contribution to fibrogenesis susceptibility in defined human cohorts.

肝纤维化是对慢性肝损伤的非特异性反应，两种最常见的原因是病毒性肝炎或酗酒，双胞胎研究和种族差异表明，与病毒性肝炎不同，遗传因素在这两种类型的易感性和进展中发挥着作用。迄今为止，尚未发现遗传与酒精性肝纤维化易感性之间存在明确关联，转化生长因子 (TGF)-β 被认为是主要的促纤维化细胞因子，可驱动各种模式的纤维化。这一核心作用使得对 TGF-β 介导的肝损伤反应的每个修饰基因座成为纤维化易感性的候选基因。该项目的目的是利用从遗传上不同的肝细胞中分离出 TGF-β 介导的损伤的修饰基因。近交系小鼠的肝细胞对 TGF-β 高度敏感，它们的死亡导致库普弗细胞的激活，随后释放炎症细胞因子以及肝星状细胞的激活。在这里，我们建议利用近交小鼠系 C57BL/6J 和 DBA/2J（也称为 BXD 重组近交系）的后代产生的遗传参考群体。细胞系将受到 TGF-β 的挑战，并且表型差异（细胞损伤、基因表达）将被量化以描述反应的差异。即 BXD 面板中的连锁分析，将使我们能够通过等位基因变异来识别对 TGF-β 产生差异反应的遗传位点。该实验框架将使我们能够评估直系同源人类区域和候选基因对确定的纤维发生易感性的贡献。人类群体。

项目成果

Systems Genetics of Liver Fibrosis: Identification of Fibrogenic and Expression Quantitative Trait Loci in the BXD Murine Reference Population

肝纤维化的系统遗传学：BXD 小鼠参考群体中纤维形成和表达数量性状位点的鉴定

• DOI: 10.1371/journal.pone.0089279
• 发表时间: 2014
• 期刊: PLoS ONE
• 影响因子: 3.7
• 作者: Hall RA;Liebe R;Hochrath K;Kazakov A;Alberts R;Laufs U;Böhm M;Fischer HP;Williams RW;Schughart K;Weber SN;Lammert F
• 通讯作者: Lammert F

A frequent variant in the human bile salt export pump gene ABCB11 is associated with hepatitis C virus infection, but not liver stiffness in a German population

人类胆汁盐输出泵基因 ABCB11 的常见变异与丙型肝炎病毒感染有关，但与德国人群的肝硬化无关

• DOI: 10.1186/1471-230x-12-63
• 发表时间: 2012-06-08
• 期刊: BMC Gastroenterology
• 影响因子: 2.4
• 作者: Müllenbach R;Weber SN;Krawczyk M;Zimmer V;Sarrazin C;Lammert F;Grünhage F
• 通讯作者: Grünhage F