Metabolic Regulation of Liver Growth

肝脏生长的代谢调节

• 批准号: 9765300
• 负责人: Wolfram Goessling
• 金额: $ 54.71万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765300
• 关键词: Adult; Affect; Blood Vessels; Carbon; Cell Proliferation; Cells; Chemicals; Cirrhosis; Complication; Coupled; DNA biosynthesis; Development; Embryo; Enzymes; Etiology; Event; G-Protein-Coupled Receptors; Genetic; Genetic Transcription; Glucose; Glutamate-Ammonia Ligase; Glutamine; Goals; Growth; Growth and Development function; Hepatic; Hip region structure; Histologic; Hormones; Incidence; Liver; Liver Cirrhosis; Liver Regeneration; Liver diseases; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of liver; Metabolic; Metabolic Pathway; Metabolism; Methodology; Modeling; Molecular; Morbidity - disease rate; Nitrogen; Nuclear; Nuclear Protein; Nucleotide Biosynthesis; Nucleotides; Nutritional; Organ Size; Outcome; Pathway interactions; Patients; Phenotype; Predisposition; Premalignant; Prevention strategy; Primary carcinoma of the liver cells; Production; Proliferating; Receptor Signaling; Regulation; Reporter; Resolution; Risk Factors; Role; Signal Pathway; Signal Transduction; Stem cells; Tissues; Transcription Coactivator; Transgenic Organisms; United States; WNT Signaling Pathway; Work; Zebrafish; biomarker discovery; cancer therapy; carcinogenesis; cell growth; chemical genetics; chronic liver disease; design; effective therapy; experimental study; glucose metabolism; glucose transport; in vivo; innovation; knockout gene; liver development; liver hyperplasia; liver injury; metabolic imaging; metabolomics; mortality; mutant; new therapeutic target; nitrogen metabolism; novel; novel therapeutics; nucleotide metabolism; organ growth; prevent; repaired; treatment strategy

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.

肝病是美国发病率和死亡率上升的常见原因：约40万 患者患有慢性肝病。肝硬化，慢性肝病的并发症是一种已建立的 肝细胞癌（HCC）发展的危险因素，该癌症会影响超过750,000名患者 在全球范围内。尽管有这种已知的因果关系，但仍没有有效的疗法来预防肝癌的生长 在肝硬化患者中。很好地描述了癌症快速增殖的能力。但是，它仍然很大程度上 未知什么使癌症能够生长，以及它们如何产生燃料和必要的蜂窝构建块 分裂。河马信号通过其转录效应子yap是器官尺寸和 包括肝脏在内的多个组织的生长。河马/YAP活动的改变可能是肝的早期事件 细胞癌的形成。但是，尚不清楚河马/YAP如何为代谢需求提供 快速细胞生长。使用斑马鱼（Danio Rerio），我们成功阐明了调节作用 肝发育和再生中的核和G蛋白偶联受体，并确定化合物 治疗有毒肝损伤。此外，我们发现了血管中葡萄糖代谢的重要作用， 干细胞形成。我们的初步工作表明，YAP增强了胚胎和成人肝脏的生长，领先 提高癌症的易感性：YAP1重新编程肝谷氨酰胺和葡萄糖代谢至 折痕氮和碳利用，可增强核苷酸生物合成以燃料增殖。 我们的长期目标是了解在肝脏过程中实现细胞生长的分子和代谢机制 发展与癌症。我们的目的是表征分子机制 PO/YAP信号传导重新编程谷氨酰胺和葡萄糖代谢以允许肝脏生长。我们的中央 pothesis是，YAP直接调节谷氨酰胺和葡萄糖代谢：它增强了合成的转录 SIS酶和转运蛋白可为从头核苷酸和DNA合成提供氮和碳，燃料 - ING细胞增殖。该假设源自我们的初步工作和对河马的认识的越来越多 肝癌的途径像差。我们工作的理由是对 河马/YAP及其对肝脏生长的代谢后果可能揭示潜在的新靶标，以防止肝脏 肝硬化患者的癌症。在特定的目标1中，我们试图定义分子机制并结合 YAP1诱导的增强谷氨酰胺合成的问题，利用特定产生的突变体和反式 基因菌株和广泛的表型，组织学和功能表征。在特定的目标2中，我们将 研究河马/YAP对葡萄糖转运和代谢增加核苷酸合成的重要性 sis。我们将部署高度创新的代谢通量和高分辨率的代谢成像来定义命运 在体内利用营养氮和碳。此外，我们将确定调制器的潜力 谷氨酰胺和葡萄糖代谢，以防止肝硬化患者的癌症形成或进展。