Foxm1b and HNF-6 regulation of liver injury response

Foxm1b和HNF-6对肝损伤反应的调节

• 批准号: 7051946
• 负责人: AI-XUAN L HOLTERMAN
• 金额: $ 12.82万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7051946
• 关键词: cell proliferation; gene expression; genetically modified animals; laboratory mouse; liver cells; liver disorder; liver regeneration; somatostatin; transcription factor

DESCRIPTION (provided by applicant): Hepatic functional reserve is an important determining factor for survival in cirrhosis. Since the liver can regenerate during the liver repair response to injury, enhancing residual functional liver mass in diseased liver by stimulating hepatocyte proliferation can accelerate repair and delay liver failure. In Foxm1b transgenic mice or GH-treated mice where premature induction of proliferation-specific Foxm1b transcription factor mediates the expression of S-and M-phase cell cycle genes, hepatocyte proliferation is accelerated during partial hepatectomy. Following bile duct ligation (BDL), bile duct cell proliferation is associated with reduced expression of hepatocyte transcription factor HNF-6. Inducing the expression of liver enriched transcription factor HNF-6 by GH or by recombinant adenovirus expressing HNF-6 cDNA also inhibits the bile duct cell proliferative response to BDL. Activated bile duct cells in turn can directly or indirectly mediate the fibrosis response to biliary obstruction. Using an animal model of biliary obstruction and fibrosis by BDL to reproduce human biliary diseases, we will test the HYPOTHESIS that increasing functional liver mass in biliary-type fibrosis in mice by 1) increasing Foxm1b-mediated hepatocyte regeneration and 2) attenuating liver fibrosis by maintaining hepatic HNF-6 expression to diminish bile duct cell activation of the profibrotic reaction enhances the liver repair response to injury. We will compare hepatocyte and biliary cell proliferation, liver function, liver fibrosis, expression of Foxm1b, HNF-6, cell cycle and profibrosis genes, and survival between Foxm1b transgenic mice with overexpressed Foxm1b in hepatocytes or the Alb-Cre Foxm1b Knock out mice with hepatocyte-specific deletion of Foxm1b Floxed allele with their littermate controls. We will also test the effect of GH-mediated induction of Foxm1b and HNF-6 on the course of biliary obstruction by evaluating similar endpoints. The potential of salvaging failed liver, improving the quality of life or extending survival of patients with liver insufficiency using these therapeutic strategies is far reaching.

描述（申请人提供）：肝功能储备是肝硬化患者生存的重要决定因素。由于肝脏在损伤修复反应中可以再生，因此通过刺激肝细胞增殖来增加病变肝脏的残余功能性肝块可以加速修复，延缓肝衰竭。在Foxm1b转基因小鼠或gh处理小鼠中，提前诱导增殖特异性Foxm1b转录因子介导- m期细胞周期基因的表达，肝部分切除术期间肝细胞增殖加速。胆管结扎（BDL）后，胆管细胞增殖与肝细胞转录因子HNF-6表达降低相关。用GH或用表达HNF-6 cDNA的重组腺病毒诱导肝脏富集转录因子HNF-6的表达也能抑制胆管细胞对BDL的增殖反应。激活的胆管细胞反过来可以直接或间接地介导胆管梗阻的纤维化反应。利用BDL引起的胆道阻塞和纤维化动物模型来复制人类胆道疾病，我们将验证以下假设：1)增加foxm1b介导的肝细胞再生，2)通过维持肝脏HNF-6的表达来减少胆管细胞纤维化反应的激活，从而增强肝脏对损伤的修复反应，从而增加小鼠胆道型纤维化的功能性肝脏质量。我们将比较肝细胞和胆道细胞的增殖、肝功能、肝纤维化、Foxm1b、HNF-6、细胞周期和纤维化基因的表达以及Foxm1b转基因小鼠和Alb-Cre Foxm1b敲除小鼠（肝细胞特异性缺失Foxm1b Floxed等位基因）与对照组的存活率。我们还将通过评估类似的终点来测试gh介导的Foxm1b和HNF-6对胆道梗阻过程的影响。使用这些治疗策略挽救衰竭肝脏、改善生活质量或延长肝功能不全患者生存的潜力是深远的。