A Balancing Act: Role of HNF4α/β-catenin in Hepatobiliary Development and Cholangiocarcinoma Formation

平衡作用：HNF4α/β-连环蛋白在肝胆发育和胆管癌形成中的作用

• 批准号: 9494830
• 负责人: Chad Michael Walesky
• 金额: $ 0.07万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-07 至 2019-09-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9494830
• 关键词: Adult; Affect; Agonist; Animal Model; Bile duct carcinoma; Biliary; Biological Assay; Biology; Cell Differentiation process; Cell Proliferation; Cells; Chemicals; Cholangiocarcinoma; Development; Diagnosis; Differentiation and Growth; Disease; Dominant-Negative Mutation; Ductal Epithelial Cell; Embryo; Endoderm; Equilibrium; Extrahepatic; Functional disorder; Genetic; Goals; Growth; HNF4A gene; Heat-Shock Response; Hepatic; Hepatobiliary; Hepatocyte; Histologic; Incidence; Inhibition of Cell Proliferation; Intrahepatic Cholangiocarcinoma; Knock-out; Liver; Liver diseases; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Mammals; Medical; Methodology; Methods; Modeling; Morphology; Mutation; Nuclear Receptors; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phenotype; Physiology; Play; Prevention; Prevention strategy; Process; Resistance; Resolution; Rodent Model; Role; Signal Pathway; Signal Transduction; Stem cells; Survival Rate; Therapeutic Intervention; Time; Transgenic Organisms; Tumor Burden; Tumor Suppressor Proteins; Work; Zebrafish; advanced disease; beta catenin; bile duct; biliary tract; cancer therapy; cell growth; chemical genetics; cholangiocyte; in vivo; in vivo imaging; insight; leukemia; liver development; mortality; mutant; new therapeutic target; novel; overexpression; prevent; screening; therapeutic development; tumor; tumor growth; tumorigenesis

PROJECT SUMMARY/ABSTRACT Cholangiocarcinoma (CC) is among the deadliest cancers worldwide, with a five-year survival rate of ~30% in intrahepatic cholangiocarcinoma (ICC) and ~50% in extrahepatic cholangiocarcinoma (ECC). It is a rare cancer, affecting ~8,500 (5,500 ICC, 3000 ECC) patients in the U.S. each year. Often cancers develop from an imbalance between signals that regulate cellular growth and differentiation. While most advances in cancer therapy have been made by inhibition of cell proliferation, the re-establishment of cell differentiation has resulted in the cure of certain forms of leukemia. In this proposal, we will focus on the interaction between hepatocyte nuclear factor 4 alpha (HNF4α), the master regulator of hepatic differentiation, and the Wnt/β- catenin signaling pathway, which enhances cell proliferation. We will use zebrafish for our studies, which has advantages as a model organism because of in vivo imaging, time resolution, and chemical screening methods not available or feasible in rodent models. Importantly, zebrafish display disease morphology and pathophysiology that is similar to mammals. We hypothesize that an HNF4α/β-catenin interaction is important in hepatobiliary development playing an important role cell fate during both development and cholangiocarcinoma formation. Our first aim is to characterize and define the importance of HNF4α/β-catenin interaction in regard to hepatobiliary development. We have recently generated novel HNF4α knockout zebrafish and are in the process of generating a heat shock-inducible HNF4α over-expression zebrafish. These models will allow us to not only define the role of HNF4α in hepatobiliary development, but, in combination with genetic and pharmacologic models of Wnt/β-catenin modulation, will allow us to characterize an interaction between these two pathways. We will use these mutants and and chemical modulators to characterize liver growth, morphology, and physiology during hepatobiliary development and assess perturbations in normal hepatic and biliary cell fate. Our second aim is to determine a role for the HNF4α/β- catenin interaction in cholangiocarcinoma formation. We will first characterize tumor incidence, progression, and mortality in zebrafish with mutations resulting in dysregulation of the HNF4α/β-catenin pathway. Further, we will utilize both genetic and pharmacologic means to re-establish a normal HNF4α/β-catenin interaction and observe changes in tumor burden. These studies will not only reveal novel mechanisms of cholangiocarcinoma pathogenesis, but also will allow us to develop new targets for therapeutic development for this devastating disease.

项目摘要/摘要 胆管癌（CC）是全球最致命的癌症之一，生存率为五年 epatitic胆管癌（ICC）的〜30％，脑外胆管癌（ECC）的〜50％。是一个 罕见的癌症，每年在美国影响约8,500名（5,500个ICC，3000名ECC）患者。癌症经常发展 来自调节细胞生长和分化的信号之间的不平衡。虽然大多数进步 癌症治疗是通过抑制细胞增殖而进行的，细胞分化的重建已有 导致治愈某些形式的白血病。在此提案中，我们将重点介绍 肝细胞核因子4α（HNF4α），肝分化的主要调节剂和Wnt/β- Catenin信号通路，可增强细胞增殖。我们将使用斑马鱼进行我们的研究 由于体内成像，时间分辨率和化学筛选方法，作为模型生物的优点 在啮齿动物模型中不可用或可行。重要的是，斑马鱼表现出疾病的形态和 类似于哺乳动物的病理生理学。我们假设HNF4α/β-catenin相互作用很重要 在肝胆管发育中，在开发和 胆管癌的形成。我们的第一个目的是表征和定义HNF4α/β-catenin的重要性 关于肝胆管发育的相互作用。我们最近产生了新型的HNF4α基因敲除 斑马鱼，正在产生热休克诱导的HNF4α过表达斑马鱼。 这些模型将使我们不仅可以定义HNF4α在肝胆管发育中的作用，而且在 与Wnt/β-catenin调制的遗传和药物模型的结合，将使我们能够表征 这两个途径之间的相互作用。我们将使用这些突变体和化学调节剂进行 表征肝脏发育和评估期间肝脏生长，形态和生理学 正常肝和胆道细胞命运中的扰动。我们的第二个目的是确定HNF4α/β-的作用 胆管癌形成中的Catenin相互作用。我们将首先表征肿瘤事件，进展， 斑马鱼的死亡率，突变导致HNF4α/β-catenin途径失调。更远， 我们将同时利用遗传和药物来重新建立正常的HNF4α/β-catenin的相互作用和 观察肿瘤负担的变化。这些研究不仅会揭示胆管癌的新机制 发病机理，但也将使我们能够为这种毁灭性的热发展开发新目标 疾病。