Hedgehog Signaling and Adult Liver Regeneration

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。目前关于肝脏再生的知识空白限制了对肝硬变和肝癌的预防和治疗，这些都是再生功能障碍(错误修复)的结果。因此，我们研究计划的最终目标是描述控制肝脏再生的机制。本申请寻求竞争性更新一个项目，该项目正在评估Hedgehog(HH)途径是肝脏再生的关键调节因子这一普遍假设。到目前为止，我们已经发现HH通路在所有类型的肝损伤中都被激活，调节再生的多个方面，并且肝星状细胞(HSC)是HH信号的关键靶点。我们发现，急性损伤会瞬间激活HH信号，并证明这是再生所必需的。相反，我们发现慢性损伤激发了持续的HH信号，使伤口愈合阶段永久化，这需要间充质细胞的丰富，从而导致纤维形成和肝癌。目前的应用建立在具有挑衅性的证据之上，即HSC可变地表现出多潜能前体细胞、肝上皮细胞和肌成纤维细胞的特征，并且HH配体调节HSC的命运决定(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，诱导糖酵解，并提示糖酵解的最终产物可能调节HSC的命运。我们将评估特定的假设，即成年HSC保持足够的可塑性，可以重新编程到其他谱系，并且HH通过精心设计有利于这种重新编程的微环境来协调肝脏再生。我们的目标是回答这些问题：1)HH信号中间产物Smoothens(Smo)在HSC重编程中起什么作用？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。我们将使用转基因小鼠，在肝损伤之前、期间和之后，允许在静止或肌成纤维细胞-HSC中有条件地删除Smo。初步数据支持这种方法的可行性，并将规范的HH信号与调节HSC重新编程的代谢事件联系起来。

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.