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酒精滥用。双胞胎研究和种族差异表明，遗传因素在两种类型的易感性和进展中发挥作用。与病毒性肝炎相反，迄今为止尚未发现遗传变异与酒精性肝纤维化易感性之间存在明确的联系。转化生长因子（TGF）-β被认为是主要的促纤维化细胞因子，响应于各种损伤模式而驱动纤维化。这种中心作用使得对TGF-β介导的肝损伤的应答的每个修饰基因座成为纤维化易感性的候选基因。本项目的目的是使用从遗传上不同的近交系小鼠品系分离的肝细胞来鉴定TGF-β介导的损伤的修饰基因。肝细胞对TGF-β高度应答。它们的死亡导致枯否细胞的活化和随后的炎性细胞因子的释放以及肝星状细胞的活化，其中生长因子和细胞外基质组分的表达增强。在这里，我们建议利用近交系C57 BL/6 J和DBA/2 J（也称为BXD重组近交系）的后代产生的遗传参考群体。将用TGF-β挑战来自这些小鼠系的遗传上不同的肝细胞，并将量化表型差异（细胞损伤、基因表达）以描述应答差异。 数量性状基因座作图，即BXD组中的连锁分析，将使我们能够通过等位基因变异鉴定对TGF-β的差异反应的遗传基因座。这个实验框架将使我们能够评估在确定的人类队列中对纤维化易感性有贡献的正交人类区域和候选基因。

项目成果

Identification of RARRES1 as a core regulator in liver fibrosis

鉴定 RARRES1 作为肝纤维化的核心调节因子

• DOI: 10.1007/s00109-012-0919-7
• 发表时间: 2012
• 期刊: Journal of Molecular Medicine
• 作者: Teufel A;Becker D;Weber SN;Dooley S;Breitkopf-Heinlein K;Maass T;Hochrath K;Krupp M;Marquardt JU;Kolb M;Korn B;Niehrs C;Zimmermann T;Godoy P;Galle PR;Lammert F
• 通讯作者: Lammert F

Common genetic variation in vitamin D metabolism is associated with liver stiffness

• DOI: 10.1002/hep.25830
• 发表时间: 2012-11-01
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Gruenhage, Frank;Hochrath, Katrin;Lammert, Frank
• 通讯作者: Lammert, Frank

Systems genetics of hepatocellular damage in vivo and in vitro: identification of a critical network on chromosome 11 in mouse.

体内和体外肝细胞损伤的系统遗传学：小鼠 11 号染色体上关键网络的鉴定

• DOI: 10.1152/physiolgenomics.00078.2013
• 发表时间: 2013
• 期刊: Physiological genomics
• 影响因子: 4.6
• 作者: Liebe R;Hall RA;Williams RW;Dooley S;Lammert F
• 通讯作者: Lammert F