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：
7863457
负责人：
Linda E GREENBAUM
金额：
$ 38.66万
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/7863457
关键词：
3-Dimensional Ablation Acute Acute Liver Failure Adult Alagille Syndrome Applications Grants 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/祖细胞对严重肝损伤做出反应的能力取决于祖细胞更新，扩张和分化的精细调整平衡。在肝脏中，包括刺猬，Wnt和Notch系统在内的发育激活的信号通路与肝祖细胞更新，组织修复和肝癌的发展有关。到目前为止，缺乏在成年肝祖细胞中调节这些途径的特定遗传工具排除了这些途径对祖细胞对肝损伤的特定贡献的分析。 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.使用这种方法，我们将剖析有助于祖细胞募集，分化和增殖的复杂自分泌和旁分泌信号事件，以及对肝损伤响应组织修复过程中纤维发生的影响。我们提出了一个信号层次结构的存在，其中有翼螺旋因子FOXL1介导刺猬和Wnt/b-catenin信号通路，用于祖细胞更新和增殖所必需的。我们预测Notch在Wnt/B-catenin的下游作用，并促进祖细胞分化向胆道谱系，也可能需要用于胆道小管形态发生。了解肝祖细胞的生物学将对急性肝衰竭，慢性肝硬化肝病和肝细胞癌癌的疗法发展具有广泛的影响。公共卫生相关性：本赠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衰竭，慢性肝硬化肝病和肝细胞癌癌的疗法发展具有广泛的影响。