Molecular response of bile duct cell to bile duct injury

胆管细胞对胆管损伤的分子反应

• 批准号: 6861016
• 负责人: AI-XUAN L HOLTERMAN
• 金额: $ 12.79万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6861016
• 关键词: Adenoviridae; bile ducts; bile obstruction; cell proliferation; epithelium; fibrosis; genetic transduction; laboratory mouse; liver cells; mentoring /mentor; microarray technology; molecular pathology; pathologic process; transcription factor

DESCRIPTION (provided by applicant) The applicant's long term goal is to develop effective strategies to prevent or attenuate the damage of biliary cirrhosis from chronic biliary obstruction based on an understanding of the genes and cellular mechanisms regulating the bile duct epithelia (BDE) function and response to biliary injury. The departments of Molecular Genetics and Surgery at the University of Illinois at Chicago are fully committed to support this endeavor by providing the candidate with protected time, core facilities usage, laboratory space and continuing research educational opportunities. The mentor is a major contributor to the field of tissue specific gene regulation and has identified several hepatocyte transcription factors essential for liver gene expression and function, including hepatocyte nuclear factor HNF-6 which is important to the performance of this project. The goal of this project is to understand the transcriptional mechanisms regulating BDE gene expression and function during the BDE proliferative response to biliary obstruction, and the role of the early BDE proliferation in the pathogenesis of liver fibrosis using the animal model of common bile duct division. HNF-6 regulates important liver specific gene expression for hepatocyte function. Since HNF-6 is abundant in the BDE and its expression is diminished in the proliferating BDE following bile duct ligation, HNF-6 may regulate the expression of differentiated genes essential to BDE function. We will overexpress HNF-6 or inhibit HNF-6 function in BDE cell lines with an adenovirus expressing a dominant negative HNF-6 protein and use differential hybridization of gene array blots of mock infected or transduced cells to identify differentiated BDE genes. We will use an adenovirus HNF-6 expression vector to transduce the BDE and restore in vivo BDE expression of HNF-6 with the aim to inhibit BDE proliferation during mouse bile duct ligation. This in vivo intervention is anticipated to impede BDE dedifferentiation and proliferation. Bile duct specific target gene mRNA and protein expression will be assessed and the effect on the development of biliary fibrosis will be determined.

描述（由申请人提供） 申请人的长期目标是制定有效的战略，以防止或 减轻慢性胆道梗阻对胆汁性肝硬化的损害 基于对基因和细胞机制的理解， 胆管上皮细胞（BDE）的功能和对胆道损伤的反应。 伊利诺伊大学分子遗传学和外科学系 在芝加哥，我们完全致力于通过提供 候选人有受保护的时间，核心设施的使用，实验室空间和 继续研究教育机会。导师是一名少校 组织特异性基因调控领域的贡献者，并已确定 几种肝细胞基因表达所必需的转录因子 和功能，包括肝细胞核因子HNF-6，这是重要的 这个项目的业绩。 这个项目的目标是了解转录机制 在BDE增殖过程中调控BDE基因的表达和功能 对胆道梗阻的反应，以及早期BDE增殖在 胆总管动物模型肝纤维化的发病机制 师. HNF-6调节重要的肝脏特异性基因表达， 肝细胞功能由于HNF-6在BDE中含量丰富，并且其表达量很高， 胆管结扎后增殖性BDE减少，HNF-6可能 调节BDE功能所必需的分化基因的表达。我们 将在BDE细胞系中过表达HNF-6或抑制HNF-6功能， 表达显性失活HNF-6蛋白的腺病毒和使用差异表达 模拟感染或转导细胞的基因阵列印迹杂交， 鉴定不同的溴化二苯醚基因。我们将使用腺病毒HNF-6表达 载体来抑制BDE并恢复HNF-6的体内BDE表达， 目的是抑制小鼠胆管结扎过程中BDE的增殖。这 预期体内干预会阻碍BDE去分化， 增殖胆管特异性靶基因mRNA和蛋白表达将 将评估对胆道纤维化发展的影响， 测定

项目成果

Transcriptional activation by growth hormone of HNF-6-regulated hepatic genes, a potential mechanism for improved liver repair during biliary injury in mice.

生长激素对 HNF-6 调节的肝基因的转录激活是改善小鼠胆道损伤期间肝脏修复的潜在机制。

• DOI: 10.1152/ajpgi.00581.2007
• 发表时间: 2008
• 期刊: American journal of physiology. Gastrointestinal and liver physiology
• 作者: Wang,Minhua;Chen,Michael;Zheng,Guoqiang;Dillard,Barney;Tallarico,Mike;Ortiz,Zorayda;Holterman,Ai-Xuan
• 通讯作者: Holterman,Ai-Xuan