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.

α-连环蛋白和Wnt信号在调节脂质稳态中的作用 项目总结： 通常仅限于胚胎发生、干细胞更新和伤口愈合的WNT信号被不适当地重新激活。 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信号的异常和脂代谢的改变都是肿瘤发生的迹象，最近 数据表明，Wnt对脂肪生成和脂肪代谢的控制可能是通过不同的机制发生的。 目前，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。目前还不可能清楚地描述Wnt在脂肪生成、脂质生成中的不同功能 合成代谢和脂肪分解代谢，因为这些过程在哺乳动物中是密不可分的。至 绕过这一限制，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(果蝇中无翼)活动的复杂性。更重要的是，独特的 果蝇生活中脂肪生成、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控和操纵这些基本过程。我们的遗传分析 Axin和α-catenin是Wnt信号通路的两个组成部分，它们已经揭示了Wnt信号调节 幼虫后期的脂肪动态平衡，与胚胎发育期间完成的脂肪生成不同。 我们已经证实Axin突变体的表型是由典型的Wnt活性的获得引起的， β-连环蛋白靶基因表达升高，编码相关酶的基因表达改变 脂肪分解代谢。通过对FDA批准的各种药物的库进行筛选，我们发现有缺陷的 脂类动态平衡和过度活跃的Wnt信号被一类多肽硼酸有效地抑制 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信号中的重要作用，正常情况下调节α-稳定性的精确机制 连环蛋白仍不清楚。因此，这项建议的目的是确定α-连环蛋白的稳定性如何， 而Wnt信号一般调节脂质分解代谢。我们将鉴定分子和细胞 通过分析脂肪沉积和脂质来控制果蝇体内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(S) 并揭示了Wnt信号如何调节脂质动员和脂质分解代谢，从而促进我们的 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。