Understanding biomineralisation in the fish dermal skeleton and its role in health and development

了解鱼类真皮骨骼中的生物矿化及其在健康和发育中的作用

• 批准号: BB/X009904/1
• 负责人: Louise Stephen
• 金额: $ 51.63万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Fellowship
• 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%2FX009904%2F1
• 关键词: Understanding; biomineralisation; fish; dermal; skeleton

By 2020 global fish production had already exceeded 179 million tonnes, and is thought to contribute £600 million to the British economy. In addition to this, zebrafish are the second most highly used species in biomedical research, after mouse. Therefore, understanding mechanisms relating to health and wellbeing of fish is vital.Much of fish development echoes that of humans and mammals in many ways. For example, the requirement for a mineralised skeleton to provide organ protection, mobility, and calcium-phosphorous homeostasis. However, unlike mammals, fish often possess a second mineralised skeleton, by way of their scales. In addition to the roles listed above, this dermal skeleton provides protection from the hostile external environment from injury and infection. Skeletal mineralisation has been shown to be detrimentally impacted in rapidly grown animals of agricultural importance, such as pigs and chickens, as well as several human disorders. In the race to produce more sustainable, cheaper protein, research into how these farming methods might affect calcium maintenance in these fish (via scale mineralisation), and how that may impact on their health and wellbeing is sorely lacking. We know that these scales mineralise in a similar way to bones, but for both bones and scales, we don't fully understand how the underlying processes lead to mineralisation. Mineralisation begins with an extracellular collagen rich matrix, which confers toughness to the tissue and acts as a scaffold on which the mineral component, hydroxyapatite (calcium - phosphate complex) is embedded, conferring stiffness to the composite material. How hydroxyapatite is initially formed has been widely debated for many years, but it is now considered to centre upon the concentration of calcium and phosphate within matrix vesicles which are themselves released by bone and scale cells. Matrix vesicles are small (100-300nm) vesicles, which contain a number of proteins responsible for the accumulation of calcium and phosphate. It has not been possible to ascertain how matrix vesicles are released from the cell. I hypothesise that matrix vesicles are released from the surface of the cell, following cytoskeletal rearrangement as identified in a number of cell membrane-based processes. I propose developing a scheme of work that will allow me to understand the importance of mineralisation in fish health and wellbeing, as well as having broader implications for the understanding of mineralisation at the molecular level, across species. In this fellowship, I will develop robust imaging techniques to image matrix vesicles. Using live cell imaging, I will manipulate proteins of interest, to elucidate their role in vesicle biogenesis and trafficking of proteins. I will further develop these imaging techniques to study matrix vesicle biogenesis in fish scales. Furthermore, I will use fish lines with a range of mineralisation phenotypes to study the importance of scale mineralisation in wound healing for fish and develop preliminary research into the extent of mineralisation changes in aquaculture species bred for meat. These studies will offer opportunities for high impact publications within this fellowship, as well as forming the basis for future senior fellowships, grant applications and studentships.

到2020年，全球鱼类的产量已经超过1.79亿吨，被认为为英国经济贡献了6亿英镑。除此之外，斑马鱼是仅次于小鼠的生物医学研究中第二大最多使用的物种。因此，了解与鱼类健康和福祉有关的机制至关重要。鱼类发育的含义在许多方面回荡了人类和哺乳动物的呼应。例如，矿化骨骼提供器官保护，迁移率和磷酸稳态的要求。但是，与哺乳动物不同，鱼通常通过尺度具有第二个矿化骨骼。除了上面列出的角色外，该皮肤骨架还提供了免受敌意外部环境免受伤害和感染的保护。骨骼矿化已被证明在迅速成长的农业重要性的动物（例如猪和鸡）以及几种人类疾病中会严重影响。在生产更可持续，廉价蛋白质的竞赛中，研究这些农业方法可能如何影响这些鱼的钙维护（通过尺度矿化）以及如何影响其健康和福祉。我们知道这些尺度以类似于骨骼的方式矿化，但是对于骨骼和鳞片，我们都不完全了解基础过程如何导致矿化。矿化始于细胞外胶原蛋白的基质，该基质赋予了对组织的韧性，并充当矿物质成分羟磷灰石（钙 - 磷酸盐络合物）的支架，嵌入了复合材料的会议刚度。最初形成的羟磷灰石是多年来广泛争论的，但现在被认为是基于基质蔬菜中钙和磷酸盐的浓度，这些钙和磷酸盐本身是由骨和尺度细胞释放的。基质蔬菜是小（100-300nm）的蔬菜，其中包含许多负责钙和磷酸盐积累的蛋白质。无法确定如何从细胞中释放基质蔬菜。我的假设是，在许多基于细胞膜的过程中发现的细胞骨架重排后，基质蔬菜是从细胞表面释放出来的。我建议制定一项工作计划，使我能够了解矿化在鱼类健康和福祉中的重要性，并对整个物种的分子水平上对矿化的理解具有更广泛的影响。在此奖学金中，我将开发出强大的成像技术来形象基质蔬菜。使用活细胞成像，我将操纵感兴趣的蛋白质，以阐明它们在囊泡生物发生和蛋白质的运输中的作用。我将进一步开发这些成像技术来研究鱼尺中的基质蔬菜生物发生。此外，我将使用具有一系列矿化表型的鱼类线来研究尺度矿化在伤口愈合中对鱼类的重要性的重要性，并将初步研究研究到饲养肉类的水产养殖物种的矿化变化程度。这些研究将为该奖学金中的高影响力出版物提供机会，并为未来的高级奖学金，赠款申请和学生提供基础。