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400，000 患者患有慢性肝病。肝硬化是慢性肝病的并发症， 肝细胞癌（HCC）发展的风险因素，每年影响超过75万患者- 全世界的。尽管有这种已知的因果关系，但没有有效的治疗方法来预防肝癌的生长 在癫痫患者中。癌症迅速增殖的能力已被充分描述。然而，在很大程度上， 目前尚不清楚是什么使癌症生长，以及它们如何产生燃料和必要的细胞构建模块， 分裂Hippo信号通过其转录效应物雅普是器官大小的主要调节因子， 包括肝脏在内的几种组织中的生长。Hippo/雅普活性的改变可能是肝细胞的早期事件， 细胞癌形成。然而，目前还不清楚河马/雅普是如何满足代谢需求的 细胞快速生长的过程。使用斑马鱼（Danio rerio），我们已经成功阐明了 核和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中的重要作用， 干细胞形成我们的初步工作表明，雅普增强胚胎和成人肝脏生长，导致 增加癌症易感性：Yap 1重新编程肝脏谷氨酰胺和葡萄糖代谢， 增加氮和碳的利用，以增强核苷酸生物合成，从而促进增殖。 我们的长期目标是了解在肝脏中细胞生长的分子和代谢机制 发展和癌症。我们的目标是描述髋关节的分子机制- po/雅普信号转导重新编程谷氨酰胺和葡萄糖代谢以允许肝脏生长。我们的中央卫生- 假设是雅普直接调节谷氨酰胺和葡萄糖代谢：它增强合成酶的转录， 为核苷酸和DNA从头合成提供氮和碳， 细胞增殖。这一假说源于我们的前期工作和对Hippo日益增长的认识 肝癌的通路畸变。我们工作的基本原理是， Hippo/雅普及其对肝脏生长的代谢后果可能揭示预防肝脏生长的潜在新靶点。 肝硬化患者的癌症。在具体目标1中，我们试图定义分子机制和结论， 序列的Yap 1诱导增强谷氨酰胺合成，利用专门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。在第二阶段，我们将 研究Hippo/雅普对葡萄糖转运和代谢的重要性，以增加核苷酸合成， 姐我们将部署高度创新的代谢通量和高分辨率代谢成像来确定命运 以及体内营养氮和碳的利用。此外，我们将确定潜在的调节剂， 谷氨酰胺和葡萄糖代谢，以预防肝硬化患者的癌症形成或进展。