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

• 批准号: 9769081
• 负责人: Jun-yuan Ji
• 金额: $ 29.7万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769081
• 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; Wound Healing; 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

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-连环蛋白和Wnt信号传导在调节脂质稳态中的作用 项目概要： Wnt信号，通常限于胚胎发生，干细胞更新和伤口愈合，是不适当的重新启动。 用于多种人类癌症，如肝细胞癌和结肠直肠癌，以及 其它疾病异常的Wnt信号传导和脂质代谢的改变都是肿瘤发生的标志，并且最近 数据表明Wnt对脂肪形成和脂质代谢的控制可能通过不同的机制发生。 目前，对这些机制仍然知之甚少，因此仍然超出了我们监测、缓解、 防止或纠正。目前尚不可能清楚地描述Wnt在脂肪形成、脂质过氧化和脂质过氧化中的单独功能。 脂肪代谢和脂质代谢，因为这些过程在哺乳动物中是不可分割地相互关联的。到 为了克服这一限制，我们使用果蝇作为主要的实验系统，它提供了无与伦比的 在体内操纵Wnt（果蝇无翅）活性的复杂性。更重要的是， 果蝇生命中脂肪生成、脂肪生成、脂肪分解和脂肪酸β-氧化的时间分离 循环使我们能够精确地监测和操纵这些基本过程。我们的基因分析 Axin和α-catenin是Wnt信号通路的两个组成部分，已经揭示了Wnt信号通路调节细胞凋亡。 在后期幼虫阶段的脂质体内平衡，独立于胚胎发生期间完成的脂肪形成。 我们已经证实，Axin突变体的表型是由典型Wnt活性的获得引起的， β-连环蛋白靶基因的表达升高，以及编码参与 脂质催化剂通过筛选各种FDA批准的药物库，我们发现， 脂质体内平衡和过度活跃的Wnt信号传导被肽硼酸有效地抑制， 蛋白酶体抑制剂。这些抑制剂的抑制作用依赖于α-连环蛋白。尽管 α-连环蛋白在Wnt信号传导中的重要作用，通常调节α-连环蛋白稳定性的精确机制， catenin仍不清楚。因此，本提案的目的是确定α-连环蛋白的稳定性， 和Wnt信号传导，调节脂质代谢。我们将鉴定出 通过分析脂肪沉积和脂质控制果蝇α-连环蛋白稳定性的机制 积累我们的研究将确定控制α-连环蛋白稳定性的分子机制 并揭示Wnt信号如何调节脂质动员和脂质分解代谢，从而推进我们的研究 了解α-catenin的肿瘤抑制作用以及Wnt信号如何调节脂质稳态。