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-连环蛋白和 Wnt 信号在调节脂质稳态中的作用 项目概要： Wnt 信号传导通常仅限于胚胎发生、干细胞更新和伤口愈合，但现在却被不恰当地重新定义。 用于多种人类癌症，如肝细胞癌和结直肠癌，以及 其他疾病。 Wnt 信号传导异常和脂质代谢改变都是肿瘤发生的迹象，最近 数据表明，Wnt 对脂肪生成和脂质代谢的控制可能通过不同的机制发生。 目前，人们对这些机制仍然知之甚少，因此仍然超出了我们监测、缓解、 预防或纠正。不可能清楚地描述 Wnt 在脂肪生成、脂质形成中的单独功能。 合成代谢和脂质分解代谢，因为这些过程在哺乳动物中是密不可分的。到 为了规避这个限制，我们使用果蝇作为主要实验系统，它提供了无与伦比的 体内操纵 Wnt（果蝇无翼）活性的复杂性。更重要的是，独特的 果蝇生命过程中脂肪生成、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监控和操纵这些基本过程。我们的基因分析 轴蛋白和 α-连环蛋白是 Wnt 信号通路的两个组成部分，揭示了 Wnt 信号通路调节 幼虫后期的脂质稳态，与胚胎发生期间完成的脂肪形成分开。 我们已经证实 Axin 突变体的表型是由经典 Wnt 活性的增加引起的， β-连环蛋白靶基因的表达升高，并改变编码相关酶的基因的表达 脂质分解代谢。通过筛选 FDA 批准的多种药物库，我们发现这两种有缺陷的药物 脂类稳态和过度活跃的 Wnt 信号传导被肽硼酸（一类）有效抑制 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，Wnt 信号传导是正常调节 α- 稳定性的精确机制 连环蛋白仍不清楚。因此，该提案的目的是确定 α-连环蛋白的稳定性，特别是， 一般来说，Wnt 信号传导调节脂质分解代谢。我们将鉴定分子和细胞 通过分析脂肪沉积和脂质控制果蝇中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-连环蛋白的肿瘤抑制作用以及 Wnt 信号如何调节脂质稳态。