Functional analysis of alkylglycerol monooxygenase; an unexpected modulator of Wnt signalling and embryogenesis

烷基甘油单加氧酶的功能分析；

• 批准号: BB/W017032/1
• 负责人: Andrea Munsterberg
• 金额: $ 53.77万
• 依托单位: University of East Anglia
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW017032%2F1
• 关键词: Functional; analysis; alkylglycerol; monooxygenase; unexpected

The big picture: for an embryo to develop normally, or an adult to function correctly, cells need to communicate with each other. This communication tells cells what they should do. The Wnt signalling pathway is a cellular communication system that plays important roles in telling cells how to behave during development of an embryo. Impaired Wnt signalling causes birth defects and contributes to numerous adult diseases, including cancers. As such, it is important we understand how the Wnt pathway works so that we can discover ways to control it and potentially find new ways to treat disease.Proteins in the Wnt pathway can be modified by cells to control how they function. Almost every step in the Wnt signalling pathway is regulated by the attachment or removal of small lipids. However, despite the importance of these lipid modifications, our understanding of how they occur and how they control Wnt signalling remains very limited. In part this is because it is difficult to find the genes making these modifications. We recently discovered that a gene named amgo, which encodes the only enzyme known to cut a particular type of lipids (called ether lipids), is a regulator of Wnt signalling and is required for normal development of the embryonic heart. We also have preliminary evidence that agmo plays an important role in development of the head, brain and muscles. Furthermore, combinations of neural, cardiac, muscle and facial abnormalities have been identified in over 25 human patients with mutations in agmo. However, we still know very little about how agmo functions, or how ether lipids are needed to form an embryo. In this project we will investigate the role of agmo in Wnt signalling and development.In Objective 1, we will determine whether agmo is really required for normal development of the head, brain and muscles? We will do this by decreasing agmo levels in tadpoles and chick embryos and using state of the art imaging and molecular biology assays to see if development of these structures is altered.In Objective 2, we will investigate how agmo affects the Wnt signalling pathway. In particular, we will use a series of molecular experiments to discover the step in the pathway where agmo is needed, and the mechanism by which it regulates Wnt signalling.Finally, in Objective 3 we will precisely measure how agmo depletion is affecting embryonic lipid metabolism. Once we have identified where the pathway goes wrong in agmo depleted frogs, we will then test whether we can correct this metabolic problem to prevent the Wnt signalling problems and birth defects.Together, these experiments will reveal how a new and powerful regulator of the Wnt pathway works. We think that our discoveries have the potential to transform our understanding of the Wnt pathway, and we hope to open up new avenues of basic and therapeutic research.

为了使胚胎正常发育，或使成年人正常发挥功能，细胞需要相互交流。这种交流告诉细胞它们应该做什么。Wnt信号通路是一种细胞通讯系统，在告诉细胞如何在胚胎发育过程中表现方面起着重要作用。Wnt信号传导受损会导致出生缺陷，并导致许多成人疾病，包括癌症。因此，我们了解Wnt通路如何工作是很重要的，这样我们就可以发现控制它的方法，并有可能找到治疗疾病的新方法。Wnt通路中的蛋白质可以被细胞修饰，以控制它们的功能。Wnt信号通路中的几乎每一步都受到小脂质的附着或去除的调节。然而，尽管这些脂质修饰的重要性，我们对它们如何发生以及它们如何控制Wnt信号传导的理解仍然非常有限。部分原因是很难找到进行这些修改的基因。我们最近发现，一种名为amgo的基因，编码唯一已知的切割特定类型脂质（称为醚脂质）的酶，是Wnt信号传导的调节因子，是胚胎心脏正常发育所必需的。我们也有初步的证据表明，agmo在头部，大脑和肌肉的发育中起着重要的作用。此外，已经在超过25名具有agmo突变的人类患者中鉴定出神经、心脏、肌肉和面部异常的组合。然而，我们仍然对agmo的功能知之甚少，或者如何形成胚胎需要醚脂。在这个项目中，我们将研究agmo在Wnt信号传导和发育中的作用。在目标1中，我们将确定agmo是否真的是头部，大脑和肌肉正常发育所必需的？我们将通过降低蝌蚪和鸡胚中的agmo水平，并使用最先进的成像和分子生物学检测来观察这些结构的发育是否改变。在目标2中，我们将研究agmo如何影响Wnt信号通路。特别是，我们将使用一系列的分子实验，以发现在途径中的步骤，需要agmo，和它调节Wnt signaling.Finally的机制，在目标3中，我们将精确测量agmo消耗是如何影响胚胎脂质代谢。一旦我们确定了在agmo耗尽的青蛙中该途径出错的地方，我们将测试我们是否可以纠正这种代谢问题，以防止Wnt信号传导问题和出生缺陷。总之，这些实验将揭示Wnt途径的一种新的强大调节剂是如何工作的。我们认为我们的发现有可能改变我们对Wnt通路的理解，我们希望开辟基础和治疗研究的新途径。