Signaling pathways and the fate of hepatic progenitor cells

信号通路和肝祖细胞的命运

基本信息

批准号：
8048131
负责人：
Linda E GREENBAUM
金额：
$ 31.82万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8048131
关键词：
3-Dimensional Ablation Acute Acute Liver Failure Adult Alagille Syndrome Applications Grants Autocrine Communication Biliary Binding Biology Cell Differentiation process Cell Proliferation Cell Survival Cell physiology Cell surface Cells Chronic Complex Data Development Diet Equilibrium Erinaceidae Event Failure Fibroblasts Fibrosis Genes Genetic Hepatic Hepatic Stellate Cell In Vitro Individual Injury Injury to Liver Ligands Ligation Liver Liver Fibrosis Liver diseases Mediating Membrane Mesenchymal Mesenchyme Modeling Molecular Morphogenesis Mouse Strains Mutate Necrosis Notch Signaling Pathway Notch and Wnt Signaling Pathway Paracrine Communication Pathway interactions Play Primary carcinoma of the liver cells Regulation Relative (related person)Role Signal Pathway Signal Transduction Source Stem cells System Tamoxifen Testing Time Tissues Winged Helix Wound Healing activating transcription factor autocrine bile duct biliary tract cholangiocyte design dietary supplements fibrogenesis forkhead protein human SMO protein in vivo inhibitor/antagonist injury and repair jagged1 protein loss of function mutant notch protein paracrine progenitor public health relevance receptor reconstruction repaired response response to injury self-renewal smoothened signaling pathway stem therapeutic development tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): The ability of hepatic stem/progenitor cells to respond to severe liver injury is dependent upon a finely tuned balance of progenitor cell renewal, expansion and differentiation. In the liver, developmentally activated signaling pathways including the hedgehog, wnt and notch systems have been implicated in the regulation of hepatic progenitor cell renewal, tissue repair and the development of hepatocellular cancer. Until now, lack of specific genetic tools to modulate these pathways in adult hepatic progenitors has precluded the analysis of the specific contribution of these pathways to the progenitor cell response to liver injury. We have discovered that the winged helix transcription factor Foxl1 uniquely marks bipotential hepatic progenitor cells and have derived both Foxl1-Cre and tamoxifen inducible Foxl1-CreERT2 mouse strains to enable gain- and loss-of-function studies through the conditional deletion of individual components of the hedgehog, wnt and notch signaling pathways in hepatic progenitor cells. Using this approach, we will dissect the complex autocrine and paracrine signaling events that contribute to progenitor cell recruitment, differentiation and proliferation as well as paracrine effects on fibrogenesis during tissue repair in response to liver injury. We propose the existence of a signaling hierarchy in which the winged helix factor Foxl1 mediates the hedgehog and wnt/b-catenin signaling pathways necessary for progenitor cell renewal and proliferation. We predict that Notch acts downstream of wnt/b-catenin and promotes progenitor cell differentiation towards the biliary lineage and may also be required for biliary tubule morphogenesis. Understanding the biology of hepatic progenitor cells will have wide-ranging implications for the development of therapeutics for acute liver failure, chronic cirrhotic liver disease and hepatocellular carcinoma. PUBLIC HEALTH RELEVANCE: The studies proposed in this grant application will elucidate the signals that regulate hepatic progenitor cells and their response to acute or chronic liver injury. Understanding the biology of hepatic progenitor cells will have wide-ranging implications for the development of therapeutics for acute liver failure, chronic cirrhotic liver disease and hepatocellular carcinoma.

描述（由申请人提供）：肝干/祖细胞响应严重肝损伤的能力取决于祖细胞更新、扩增和分化的精细调节平衡。在肝脏中，包括hedgehog、wnt和notch系统在内的发育激活信号通路与肝祖细胞更新、组织修复和肝细胞癌发展的调节有关。到目前为止，缺乏调节成年肝祖细胞中这些途径的特定遗传工具，无法分析这些途径对祖细胞对肝损伤反应的具体贡献。我们发现翼状螺旋转录因子 Foxl1 独特地标记双能肝祖细胞，并衍生出 Foxl1-Cre 和他莫昔芬诱导性 Foxl1-CreERT2 小鼠品系，通过条件性删除单个组件，能够进行功能获得和丧失的研究。肝祖细胞中的刺猬蛋白、WNT 和 Notch 信号通路。使用这种方法，我们将剖析复杂的自分泌和旁分泌信号事件，这些信号事件有助于祖细胞的募集、分化和增殖，以及在响应肝损伤的组织修复过程中旁分泌对纤维发生的影响。我们提出存在一个信号传导层次，其中翼状螺旋因子 Foxl1 介导祖细胞更新和增殖所需的刺猬和 wnt/b-连环蛋白信号传导途径。我们预测Notch作用于wnt/b-连环蛋白的下游并促进祖细胞向胆管谱系分化，并且也可能是胆管形态发生所必需的。了解肝祖细胞的生物学将对急性肝功能衰竭、慢性肝硬化肝病和肝细胞癌的治疗方法的开发产生广泛的影响。公共健康相关性：本拨款申请中提出的研究将阐明调节肝祖细胞的信号及其对急性或慢性肝损伤的反应。了解肝祖细胞的生物学将对急性肝功能衰竭、慢性肝硬化肝病和肝细胞癌的治疗方法的开发产生广泛的影响。