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; 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.

大局：要使胚胎正常发展，或者成年以正常运行，细胞需要相互通信。这种通信告诉细胞他们应该做什么。 Wnt信号通路是一个细胞通信系统，在告诉细胞在胚胎过程中如何表现起着重要作用。 Wnt信号受损会导致先天缺陷，并导致包括癌症在内的许多成人疾病。因此，重要的是我们了解Wnt途径的工作原理，以便我们可以找到控制它的方法并可能找到新的方法来治疗疾病。Wnt途径中的蛋白质可以通过细胞来修改以控制它们的功能。 Wnt信号通路中的几乎每个步骤都通过小脂质的附着或去除来调节。但是，尽管这些脂质修饰的重要性很重要，但我们对它们的发生方式以及它们如何控制Wnt信号的理解仍然非常有限。部分原因是很难找到进行这些修饰的基因。我们最近发现，一个名为Amgo的基因编码唯一已知的酶切割特定类型的脂质（称为乙醚脂质），是Wnt信号传导的调节剂，是胚胎心脏正常发育所必需的。我们还有初步证据表明，AGMO在头部，大脑和肌肉的发育中起着重要作用。此外，在AGMO突变的25例人类患者中已经确定了神经，心脏，肌肉和面部异常的组合。但是，我们仍然对AGMO的功能或如何形成胚胎的醚脂质的功能或乙醚脂质如何了解。在这个项目中，我们将研究AGMO在Wnt信号传导和开发中的作用。在目标1中，我们将确定AGMO是否真的需要正常的头部，大脑和肌肉发育？我们将通过降低t和雏鸡胚胎的新生物水平，并使用最先进的成像和分子生物学测定法来查看这些结构的发展是否改变。在目标2中，我们将研究AGMO如何影响Wnt信号通路。特别是，我们将使用一系列分子实验来发现需要AGMO的途径中的步骤，以及它调节Wnt信号的机制。从目标3中，我们将精确地衡量AGMO耗竭如何影响胚胎脂质的代谢。一旦我们确定了AGMO耗尽青蛙的路径出错的位置，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。我们认为，我们的发现有可能改变我们对WNT途径的理解，我们希望开放基本和治疗研究的新途径。