Hedgehog Signaling and Adult Liver Regeneration

Hedgehog 信号传导和成人肝脏再生

• 批准号: 8366959
• 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/8366959
• 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; 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. PUBLIC HEALTH RELEVANCE: Liver cirrhosis and cancer are important causes of human suffering and death worldwide. Our work has identified previously-unsuspected mechanisms that control the development of these problems. These discoveries pave the way for new strategies to prevent and treat cirrhosis and liver cancer, which are the major bad outcomes of all types of chronic liver disease.

描述（由申请人提供）：肝损伤的结果取决于修复的成功或失败。目前关于肝脏如何再生的知识差距限制了肝硬化和肝癌的预防和治疗，这是再生功能障碍（错误修复）的结果。因此，我们研究计划的最终目标是描绘控制肝脏再生的机制。本申请寻求对一个项目进行竞争性更新，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，我们发现 Hh 通路在所有类型的肝损伤期间都会被激活，调节再生的多个方面，并且肝星状细胞 (HSC) 是 Hh 信号传导的关键靶标。我们发现急性损伤会短暂激活 Hh 信号传导，并证明这是再生所必需的。相反，我们发现慢性损伤会激发持续的 Hh 信号，使伤口愈合阶段永久化，从而需要间充质细胞富集，从而导致纤维形成和肝癌。本申请建立在令人兴奋的证据之上，即HSC不同程度地表现出多能祖细胞、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 Hh 调节的代谢开关，该开关可诱导糖酵解，并表明糖酵解终产物可能会调节 HSC 的命运。我们将评估特定假设，即成年 HSC 保留足够的可塑性以重编程为其他谱系，并且 Hh 通过营造有利于这种重编程的微环境来协调肝脏再生。我们的目标是回答以下问题：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错误修复。我们将使用允许在肝损伤之前、期间和之后在静止或肌纤维母细胞 HSC 中条件性删除 Smo 的转基因小鼠。初步数据支持这种方法的可行性，并将规范的 Hh 信号传导与调节 HSC 重编程的代谢事件联系起来。 公共卫生相关性：肝硬化和癌症是全世界人类痛苦和死亡的重要原因。我们的工作已经确定了以前未曾怀疑过的控制这些问题发展的机制。这些发现为预防和治疗肝硬化和肝癌的新策略铺平了道路，肝硬化和肝癌是所有类型慢性肝病的主要不良后果。