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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：
10001358
负责人：
Jun-yuan Ji
金额：
$ 5.82万
依托单位：
TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
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 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10001358
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 Hyperactive behavior 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