Hedgehog Signaling and Adult Liver Regeneration

Hedgehog 信号传导和成人肝脏再生

• 批准号: 8636452
• 负责人: ANNA MAE ELIZABETH DIEHL
• 金额: $ 34.15万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636452
• 关键词: Acute; Adult; Bile fluid; Blood; Cell Fraction; Cells; Cessation of life; Characteristics; Chronic; Cirrhosis; Communities; Data; Development; Embryonic Development; Endothelial Cells; Environment; Epithelial; Epithelial Cells; Erinaceidae; Event; Exhibits; Failure; Gene Expression; Genes; Genetic; Glycolysis; Goals; Growth; Hepatic Stellate Cell; Hepatocyte; Human; Immune; Injury; Knowledge; Ligand Binding; Ligands; Link; Liver; Liver Cirrhosis; Liver Fibrosis; Liver Regeneration; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Mesenchymal; Mesenchyme; Mesoderm; Mesothelium; Metabolic; Metabolism; Multipotent Stem Cells; Myofibroblast; Natural regeneration; Outcome; Paracrine Communication; Pathway interactions; Phase; Phenotype; Prevention; Prevention therapy; Process; Production; Publishing; Reporting; Research; Role; Stem cells; Stress; Tissues; Transgenic Mice; Work; Wound Healing; cell type; cholangiocyte; chronic liver disease; epithelial to mesenchymal transition; fetal; fibrogenesis; human SMO protein; improved; liver injury; multipotent cell; prevent; progenitor; programs; receptor; repaired; response; smoothened signaling pathway; stem; success

DESCRIPTION (provided by applicant): The outcomes of liver injury are dictated by the success or failure of repair. Current gaps in knowledge about how the liver regenerates limit prevention and treatment of cirrhosis and liver cancer, which are outcomes of dysfunctional regeneration (mis-repair).Thus, the ultimate goal of our research program is to delineate mechanisms that control liver regeneration. The present application seeks competitive renewal of a project that is evaluating the general hypothesis that the Hedgehog (Hh) pathway is one of the key regulators of liver regeneration. Thus far, we've discovered that the Hh pathway is activated during all types of liver injury, regulates multiple facets of regeneration, and that hepatic stellate cells (HSC) are critical targets of Hh signaling. We showed that acute injury transiently activates Hh signaling and proved this is required for regeneration. Conversely, we found that chronic injury provokes sustained Hh signaling that perpetuates phases of wound healing that necessitate mesenchymal cell enrichment and hence, fibrogenesis and liver cancer. The present application is built upon provocative evidence that HSC variably exhibit features of multipotent progenitors, liver epithelial cells, and myofibroblasts, and that Hh ligands modulate HSC fate decisions (i.e., reprogramming). Our latest data indicate that HSC reprogramming involves a Hh-regulated metabolic switch that induces glycolysis, and suggest that glycolytic end-products may modulate HSC fate. We will evaluate the SPECIFIC HYPOTHESIS that adult HSC retain sufficient plasticity to be reprogrammed to other lineages, and that Hh orchestrates liver regeneration by crafting a microenvironment that favors such reprogramming. Our Aims are to answer these questions: 1) What is the role of the Hh signaling intermediate, Smoothened (Smo), in HSC reprogramming? 2) How do changes in intermediatry metabolism regulate Smo- mediated HSC reprogramming? 3) How do Hh-regulated changes in HSC phenotype impact liver regeneration and mis-repair. We will use transgenic mice that permit conditional deletion of Smo in quiescent or myofibroblastic-HSC before, during, and after liver injury.Preliminary data support the feasibility of this approach and link canonical Hh signaling with metabolic events that regulate HSC reprogramming.

描述（由申请人提供）：肝损伤的结局取决于修复的成功或失败。目前对肝脏再生的认识不足限制了肝硬化和肝癌的预防和治疗，这是功能失调再生（错误修复）的结果。因此，我们研究计划的最终目标是描述控制肝脏再生的机制。本申请寻求项目的竞争性更新，该项目正在评估Hedgehog（Hh）途径是肝再生的关键调节因子之一的一般假设。到目前为止，我们已经发现Hh通路在所有类型的肝损伤期间被激活，调节再生的多个方面，并且肝星状细胞（HSC）是Hh信号传导的关键靶点。我们发现，急性损伤瞬时激活Hh信号，并证明这是再生所必需的。相反，我们发现慢性损伤引起持续的Hh信号传导，使伤口愈合的阶段持续下去，这需要间充质细胞富集，因此，纤维化和肝癌。本申请是建立在刺激性证据的基础上的，该证据表明HSC Hh表现出多能祖细胞、肝上皮细胞和肌成纤维细胞的特征，并且Hh配体调节HSC命运决定（即，重编程）。我们的最新数据表明，HSC重编程涉及一个Hh调节的代谢开关，诱导糖酵解，并表明糖酵解终产物可能调节HSC的命运。我们将评估特定的假设，即成年HSC保留足够的可塑性以重新编程为其他谱系，并且Hh通过制作有利于这种重新编程的微环境来协调肝再生。我们的目的是回答这些问题：1）Hh信号中间体Smoothened（Smo）在HSC重编程中的作用是什么？2)中间代谢的变化如何调节Smo介导的HSC重编程？3)Hh调节的HSC表型变化如何影响肝再生和误修复我们将使用转基因小鼠，允许有条件地删除Smo在静止或肌纤维母细胞-HSC之前，期间，和之后liverinjure.Preliminary数据支持这种方法的可行性，并链接规范的Hh信号与代谢事件，调节HSC重编程。