Role of alpha-catenin and Wnt signaling in regulating lipid homeostasis

α-连环蛋白和 Wnt 信号在调节脂质稳态中的作用

基本信息

批准号：
10248472
负责人：
Jun-yuan Ji
金额：
$ 30.4万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10248472
关键词：
26S proteasome Abbreviations Address Adipocytes Advanced Malignant Neoplasm Affect Anabolism Animal Model Attenuated Biochemical Boronic Acids C-terminal Cachexia Catabolism Cells Chronic Colorectal Cancer Complex Data Defect Degradation Pathway Deposition Development Diabetes Mellitus Disease Drosophila genus Drosophila melanogaster Economic Burden Ectopic Expression Embryonic Development Enzymes FDA approved Family Dasypodidae Fat Body Fatty Acids Fatty acid glycerol esters Felis catus Gene Expression Gene Proteins Genes Genetic Goals Heart Diseases Homeostasis Homologous Gene Human Hyperactivity Investigation Kidney Diseases Knowledge Libraries Life Cycle Stages Ligase Link Lipase Lipid Mobilization Lipids Lipolysis Lung diseases Lysosomes Malignant Neoplasms Mammalian Cell Mammals Metabolic Diseases Molecular Monitor Nonesterified Fatty Acids Obesity Pathway interactions Patients Peptides Pharmaceutical Preparations Phenotype Primary carcinoma of the liver cells Process Proteasome Inhibitor Proteins Proteomics Risk Factors Role Signal Pathway Signal Transduction System Tissues Triglycerides Tumor Suppressor Proteins WNT Signaling Pathway Work adipocyte differentiation alpha catenin arm base beta catenin cancer type developmental genetics fly genetic analysis hepatocyte growth factor-regulated tyrosine kinase substrate in vivo inhibitor/antagonist lipid biosynthesis lipid metabolism mutant oxidation prevent protein expression public health relevance screening social stem cell division transcription factor transcriptome sequencing tumor tumorigenesis ubiquitin-protein ligase wound healing

项目摘要

Title: Role of α-catenin and Wnt signaling in regulating lipid homeostasis Project Summary: Wnt signaling, normally limited to embryogenesis, stem cell renewal and wound healing, is inappropriately re- employed in a variety of human cancers, such as hepatocellular carcinoma and colorectal cancer, as well as other diseases. Aberrant Wnt signaling and altered lipid metabolism are both signs of oncogenesis, and recent data suggest that Wnt control of adipogenesis and lipid metabolism may occur through separate mechanisms. Currently, the mechanisms remain poorly understood, and so remain outside of our ability to monitor, mitigate, prevent, or correct. It has been impossible to clearly delineate separate functions of Wnt in adipogenesis, lipid anabolism, and lipid catabolism, because these processes are inextricably interconnected in mammals. To circumvent this limitation, we use Drosophila as a primary experimental system, which provides unparalleled sophistication in manipulating Wnt (Wingless in Drosophila) activity in vivo. More importantly, the unique temporal separation of adipogenesis, lipogenesis, lipolysis, and fatty acid β-oxidation during the Drosophila life cycle allows us to precisely monitor and manipulate these fundamental processes. Our genetic analyses of Axin and α-catenin, two components of the Wnt signaling pathway, have revealed that Wnt signaling regulates lipid homeostasis during the late larval stage, separately from adipogenesis completed during embryogenesis. We have confirmed that the phenotypes of Axin mutants are caused by a gain of the canonical Wnt activity, elevated expression of β-catenin target genes, and altered expression of genes encoding enzymes involved in lipid catabolism. By screening a library of diverse FDA-approved drugs, we discovered that both the defective lipid homeostasis and the hyperactive Wnt signaling are potently suppressed by peptide boronic acids, a class of proteasome inhibitors. The suppressive effects of these inhibitors are dependent on α-catenin. Despite the important role of α-catenin in Wnt signaling, the precise mechanisms that normally regulate the stability of α- catenin remain unclear. Thus the objective of this proposal is to determine how α-catenin stability in particular, and Wnt signaling in general, regulates lipid catabolism. We will identify the molecular and cellular mechanisms that control the stability of α-catenin in Drosophila by analyzing fat deposition and lipid accumulation. Our investigations will define the molecular mechanism(s) that control the stability of α-catenin and reveal how Wnt signaling regulates lipid mobilization and lipid catabolism, thereby advancing our understanding of the tumor suppressive effects of α-catenin and how Wnt signaling regulates lipid homeostasis.

标题：α-catenin和Wnt信号在调节脂质稳态中的作用项目摘要： Wnt信号传导通常仅限于胚胎发生，干细胞的更新和伤口愈合，是不当重复的从事各种癌症，例如肝细胞癌和结直肠癌，以及其他疾病。异常的Wnt信号传导和脂质代谢改变是肿瘤发生的迹象，最近数据表明，可以通过单独的机制来控制脂肪形成和脂质代谢。目前，这些机制仍然很少理解，因此仍然超出了我们监测，减轻，减轻，预防或纠正。不可能清楚地描绘脂肪形成中Wnt的单独功能代谢和脂质分解代谢，因为这些过程在哺乳动物中密不可分。到规避此限制，我们使用果蝇作为主要实验系统，该系统提供了无与伦比的在体内操纵Wnt（果蝇中无翅）活性的软化。更重要的是，独特果蝇寿命期间脂肪生成，脂肪生成，脂解和脂肪酸β-氧化的暂时分离周期使我们能够精确监视和操纵这些基本过程。我们对 Wnt信号通路的两个组成部分Axin和α-catenin揭示了Wnt信号传导调节幼虫晚期的脂质稳态，与胚胎发生过程中的脂肪生成分开。我们已经证实，轴蛋白突变体的表型是由规范Wnt活性的增益引起的 β-catenin靶基因的表达升高，并改变了涉及的酶的基因表达脂质分解代谢。通过筛选潜水员FDA批准的药物的库，我们发现两者都有缺陷脂质体内稳态和多动WNT信号传导可能被辣椒酸抑制，一个类别蛋白酶体抑制剂。这些抑制剂的抑制作用取决于α-catenin。尽管有 α-catenin在Wnt信号传导中的重要作用，这通常调节α-的稳定性的精确机制蛋白链蛋白仍然不清楚。该提议的目的是确定α-钙蛋白稳定性如何，尤其是如何一般而言，Wnt信号传导调节脂质分解代谢。我们将确定分子和细胞通过分析脂肪沉积和脂质来控制果蝇中α-catenin稳定性的机制积累。我们的投资将定义控制α-catenin稳定性的分子机制并揭示Wnt信号如何调节脂质动员和脂质分解代谢，从而提高我们了解α-catenin的肿瘤抑制作用以及Wnt信号如何调节脂质稳态。