Assessing defects in embryonic development due to loss of protein fucosylation

评估由于蛋白质岩藻糖基化缺失导致的胚胎发育缺陷

• 批准号: RGPIN-2019-04680
• 负责人: French, Curtis
• 金额: $ 2.19万
• 依托单位: Memorial University of Newfoundland
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=683355
• 关键词: Assessing; defects; embryonic; development; due

Lay Summary***Protein fucosylation is an evolutionary conserved process that occurs in all animals. Protein fucosylation refers to the addition of sugar (fucose) molecules to target proteins in order to ensure their proper function. We use the small brackish fish, (Danio rerio) to study what happens to an embryo when protein fucosylation is disrupted. Upon making a mutation in a gene required for protein fucosylation in these fish, their embryos developed cerebral hemorrhages. This indicates that protein fucosylation is required to build stable, functioning blood vessels. We use the zebrafish to try and figure how the gene, and protein fucosylation in general, is required to build blood vessels. ******Zebrafish with defects in protein fucosylation have a number of other problems in addition to cerebral hemorrhages. For example, their tails are bent and they swim in circles. These problems, and the cerebral hemorrhages, can all be explained by defective cilia. Cilia are important structures located on almost all of our bodies cells, and are critically important for normal embryo development. Cilia for example, can beat and move fluid through the spinal columns, and defects in these cilia are known to cause bent tails in fish. Zebrafish also have cilia on the outside of their body that detect changes in water currents, and defects in these cilia can cause circular swimming behavior. Finally, cilia point into our blood vessels, and play an important role in vessel development and the regulation of blood pressure. Defects in these cilia are known to cause cerebral hemorrhages. In my lab, we are able to visualize cilia in our mutant zebrafish that lack protein fucosylation, to see if there are any defects. We look at the cilia in blood vessels, in the spinal column, and on the outside of the body to see if defective cilia are responsible for the cerebral hemorrhages, bent tails, and circular swimming behavior in our protein fucosylation deficient zebrafish.******This work is important to help us understand how cilia function and why they are important, and help us to learn about how they might be important in humans. For example, defects in cilia that cause bent tails in zebrafish can cause scoliosis (bent spines) in humans. Humans have cilia in our ears that help us hear, and are almost identical in structure to the cilia on the outside of zebrafish that help them swim. Humans can also be at increased risk for cerebral blood vessel defects due to problems with cilia, so our zebrafish serve as a useful tool to understand the underlying biological problems that lead to vascular diseases such as stroke. Lastly, as all animals require protein fucosylation, our work can translate across scientific disciplines to give us clues as to how other animals use protein fucosylation in order to maintain normal body function. **

* 蛋白质岩藻糖基化是发生在所有动物中的进化保守过程。蛋白质岩藻糖基化是指将糖（岩藻糖）分子添加到靶蛋白质以确保其正常功能。 我们使用小的咸水鱼（Danio rerio）来研究当蛋白质岩藻糖基化被破坏时胚胎会发生什么。当这些鱼的蛋白质岩藻糖基化所需的基因发生突变时，它们的胚胎就会发育成大脑萎缩。这表明蛋白质岩藻糖基化是建立稳定的功能性血管所必需的。我们用斑马鱼来尝试弄清楚基因和蛋白质岩藻糖基化是如何形成血管的。** 蛋白质岩藻糖基化缺陷的斑马鱼除了大脑受损外还有许多其他问题。例如，它们的尾巴是弯曲的，它们绕着圈游泳。这些问题，以及大脑萎缩，都可以用纤毛缺陷来解释。纤毛是几乎所有人体细胞上的重要结构，对正常胚胎发育至关重要。例如，纤毛可以通过脊柱跳动和移动液体，而这些纤毛的缺陷已知会导致鱼类弯曲的尾巴。斑马鱼身体外部也有纤毛，可以检测水流的变化，这些纤毛的缺陷会导致循环游泳行为。最后，纤毛指向我们的血管，并在血管发育和血压调节中发挥重要作用。已知这些纤毛的缺陷会导致脑血管病。 在我的实验室里，我们能够观察到缺乏蛋白质岩藻糖基化的突变斑马鱼的纤毛，看看是否有任何缺陷。我们观察血管中的纤毛，脊柱中的纤毛，以及身体外部的纤毛，看看有缺陷的纤毛是否是我们的蛋白质岩藻糖基化缺陷斑马鱼的大脑发育，弯曲尾巴和循环游泳行为的原因。这项工作对于帮助我们了解纤毛的功能以及为什么它们很重要很重要，并帮助我们了解它们在人类中的重要性。例如，导致斑马鱼尾巴弯曲的纤毛缺陷可能导致人类脊柱侧凸（脊柱弯曲）。人类耳朵里有纤毛，帮助我们听到声音，并且在结构上几乎与斑马鱼外部帮助它们游泳的纤毛相同。 由于纤毛问题，人类也可能增加脑血管缺陷的风险，因此我们的斑马鱼可以作为一种有用的工具来了解导致中风等血管疾病的潜在生物学问题。最后，由于所有动物都需要蛋白质岩藻糖基化，我们的工作可以跨学科翻译，为我们提供其他动物如何使用蛋白质岩藻糖基化以维持正常身体功能的线索。**