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: 10375985
• 负责人: Jun-yuan Ji
• 金额: $ 44.37万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 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/10375985
• 关键词: Role; alpha; catenin; Wnt; signaling

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。 数据表明，可能通过稀疏机制来控制脂肪形成和脂质代谢。 目前，这些机制仍然很贫穷，因此，我们的监测能力仍然不超出我们的能力，减轻，减轻， 预防或纠正。 代谢性和脂质分解代谢，因为这些过程是密不可分的 规避此限制，我们使用果蝇作为主要实验系统 操纵wnt（果蝇中无翅）的精致活动。 脂肪生成，脂肪生成，脂解和脂肪酸β-典型的β-异常的时间分离 周期使我们能够精确监视和操纵这些基本过程。 Wnt信号通路的两个组成部分的Axin和α-catenin河已经河水调节了Wnt信号的调节 幼虫阶段的脂质体内平衡，与胚胎发生过程中完成的脂肪生成分开。 我们已经证实，轴肌的表型是由规范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。 脂质稳态和多动Wnt信号传导被肽硼酸有效抑制 蛋白酶体抑制剂的抑制作用取决于α-catenin。 α-cateninin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 cateninininininininin nort Clean尚不清楚。 Wnt信号通常调节脂质分解代谢。 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 我们的研究将定义控制α-catenin的稳定性的分子机制 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。