Metabolic Regulation of Liver Growth

肝脏生长的代谢调节

基本信息

批准号：
9315803
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
项目类别：
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/9315803
关键词：
Adult Affect Blood Vessels Carbon Cell Proliferation Cells Chemicals Cirrhosis Complication DNA biosynthesis Development Embryo Enzymes Etiology Event G Protein-Coupled Receptor Signaling 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 Precancerous Conditions Predisposition Premalignant Prevention strategy Primary carcinoma of the liver cells Production Proliferating 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

项目摘要

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：大约 400,000 患者患有慢性肝病。肝硬化是慢性肝病的一种并发症，已被证实发生肝细胞癌 (HCC) 的危险因素，每年影响超过 750,000 名患者遍布全球。尽管存在这种已知的因果关系，但仍然没有有效的疗法来预防肝癌的生长在肝硬化患者中。癌症快速增殖的能力已得到充分描述。然而，这在很大程度上仍然是未知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来划分。 Hippo 信号通过其转录效应子 Yap 是器官大小和器官大小的主要调节因子。在包括肝脏在内的多种组织中生长。 Hippo/Yap 活动的改变可能是肝细胞疾病的早期事件细胞癌的形成。然而，目前尚不清楚 Hippo/Yap 如何满足代谢需求细胞快速生长。利用斑马鱼（Danio rerio），我们成功地阐明了核和 G 蛋白偶联受体在肝脏发育和再生中的作用，并鉴定了化合物治疗中毒性肝损伤。此外，我们发现葡萄糖代谢在血管和干细胞形成。我们的初步工作表明，Yap 可以促进胚胎和成人肝脏的生长，从而导致增加癌症易感性：Yap1 重新编程肝脏谷氨酰胺和葡萄糖代谢增加氮和碳的利用，增强核苷酸生物合成，促进增殖。我们的长期目标是了解肝脏过程中细胞生长的分子和代谢机制发育和癌症。我们的目标是表征髋关节的分子机制 po/Yap 信号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hy- 假设 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 酶和转运蛋白为从头核苷酸和 DNA 合成提供氮和碳，细胞增殖。这个假设源自我们的前期工作和对河马的日益认可肝癌中的通路异常。我们工作的基本原理是详细了解 Hippo/Yap 及其对肝脏生长的代谢影响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，我们寻求定义分子机制和结果 Yap1 诱导增强谷氨酰胺合成的序列，利用特异生成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 对于葡萄糖转运和代谢以增加核苷酸合成的重要性姐姐。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以及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化患者的癌症形成或进展。