Metabolic Regulation of Liver Growth

肝病是美国发病率和死亡率上升的常见原因：约40万人 患者患有慢性肝病。肝硬变是慢性肝病的一种并发症 发展为肝细胞癌的危险因素，每年影响超过75万名患者- 在世界范围内。尽管有这种已知的因果关系，但目前还没有有效的治疗方法来防止肝癌的生长。 在肝硬变患者中。癌症迅速扩散的能力得到了很好的描述。然而，它在很大程度上仍然是 未知是什么使癌症生长，以及它们是如何产生燃料和必要的细胞构建块的 分裂。河马信号，通过其转录效应器YAP，是器官大小和 在几个组织中生长，包括肝脏。河马/YAP活动的改变可能是肝病的早期事件- 细胞癌的形成。然而，目前还不清楚河马/YAP是如何提供代谢需求的 细胞的快速生长。利用斑马鱼(Danio Rerio)，我们成功地阐明了 核蛋白和G蛋白偶联受体在肝脏发育和再生中的作用，并鉴定了 治疗中毒性肝损伤。此外，我们发现葡萄糖代谢在血管和血管中的重要作用 干细胞的形成。我们的初步工作表明，YAP促进胚胎和成年肝脏的生长，领先于 增加癌症易感性：YAP1将肝脏谷氨酰胺和葡萄糖代谢重新编程为- 提高氮和碳的利用率，以促进核苷酸生物合成，从而促进核扩散。 我们的长期目标是了解在肝脏中促进细胞生长的分子和代谢机制。 发展和癌症。我们在这里的目标是描述Hip-Hip- PO/YAP信号对谷氨酰胺和葡萄糖代谢进行重新编程，以允许肝脏生长。我们的中央- 假说是YAP直接调节谷氨酰胺和葡萄糖代谢：它增强合成酶的转录- SIS酶和转运体为从头合成核苷酸和DNA提供氮和碳，燃料- ING细胞增殖。这一假说源于我们的初步工作和对河马越来越多的认识 肝癌中的通路异常。我们工作的基本原理是，详细了解 河马/YAP及其对肝脏生长的代谢影响可能揭示潜在的预防肝脏的新靶点 肝硬变患者的癌症。在具体目标1中，我们试图定义分子机制，并得出以下结论： YAP1诱导的谷氨酰胺合成增强序列，利用特定产生的突变体和反式- 基因菌株和广泛的表型、组织学和功能特征。在具体目标2中，我们将 研究Hippo/YAP对葡萄糖转运和代谢的重要性，以增加核苷酸合成。 姐姐。我们将部署高度创新的代谢流和高分辨率代谢成像来定义命运 体内营养氮和碳的利用。此外，我们将确定调制器的潜力 谷氨酰胺和葡萄糖代谢可预防肝硬变患者癌症的形成或进展。

Liver disease is a common cause of rising morbidity and mortality in the United States: approximately 400,000 patients suffer from chronic liver disease. Cirrhosis, a complication of chronic liver disease is an established risk factor for the development of hepatocellular carcinoma (HCC), which affects over 750,000 patients annual- ly world-wide. Despite this known causality, there are no effective therapies to prevent liver cancer growth in cirrhotic patients. The ability of cancers to proliferate rapidly is well described. It is, however, still largely unknown what enables cancers to grow and how they generate the fuel and necessary cellular building blocks to divide. Hippo signaling, through its transcriptional effector Yap, is a major regulator of organ size and growth in several tissues, including the liver. Alterations in Hippo/Yap activity may be early events in hepato- cellular carcinoma formation. It is unclear, however, how Hippo/Yap provides for the metabolic demands of rapid cell growth. Using the zebrafish (Danio rerio), we have successfully elucidated regulatory roles for nuclear and G protein-coupled receptors in liver development and regeneration, and identified compounds to treat toxic liver injury. Further, we discovered an important role for glucose metabolism in blood vessel and stem cell formation. Our Preliminary Work shows that Yap enhances embryonic and adult liver growth, leading to increased cancer susceptibility: Yap1 reprograms hepatic glutamine and glucose metabolism to in- crease nitrogen and carbon utilization for enhanced nucleotide biosynthesis to fuel proliferation. Our long-term goal is to understand the molecular and metabolic mechanisms enabling cell growth during liver development and cancer. Our objective here is to characterize molecular mechanisms by which Hip- po/Yap signaling reprograms glutamine and glucose metabolism to permit liver growth. Our central hy- pothesis is that Yap directly modulates glutamine and glucose metabolism: it enhances transcription of synthe- sis enzymes and transporters to provide nitrogen and carbon for de novo nucleotide and DNA synthesis, fuel- ing cell proliferation. This hypothesis is derived from our preliminary work and increasing recognition of Hippo pathway aberrations in liver cancer. The rationale for our work is that a detailed understanding of the impact of Hippo/Yap and its metabolic consequences for liver growth may reveal potential new targets to prevent liver cancer in patients with cirrhosis. In Specific Aim 1, we seek to define the molecular mechanisms and conse- quences of Yap1-induced enhanced glutamine synthesis, utilizing specifically generated mutants and trans- genic strains and extensive phenotypic, histological and functional characterization. In Specific Aim 2, we will investigate the importance of Hippo/Yap for glucose transport and metabolism to increase nucleotide synthe- sis. We will deploy highly innovative metabolic flux and high-resolution metabolic imaging to define the fate and utilization of nutritional nitrogen and carbon in vivo. Further, we will identify the potential of modulators of glutamine and glucose metabolism to prevent cancer formation or progression in patients with cirrhosis.