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Metabolic refinement of sensory cell development

感觉细胞发育的代谢精细化

基本信息

批准号：
BB/V006371/1
负责人：
Zoe Francesca Mann
金额：
$ 92.74万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FV006371%2F1
关键词：
Metabolic refinement sensory cell development

项目摘要

Our ability to understand speech, listen to music or hear the high pitch of a mosquito, relies on highly specialised cells in our inner ears called hair cells (HCs). These cells are named so because of the presence of hair-like bundles on their apical surfaces made of a special protein called Actin. Every sound we hear is composed of many different frequencies. The primary job of HCs is to break down complex sounds, like speech and music, into their individual frequency components. This process takes place along the length of the hearing organ, the cochlea. One way to envisage this, is to picture HCs in the cochlea much like the keys on a piano, where each cell, or key, responds to a specific frequency or note. Developmental errors in how HCs form or damage and loss of HCs causes permanent hearing loss. There are currently no biological therapies available to replace these cells once they are lost. Successfully identifying the factors needed to generate functionally viable HCs requires a detailed understanding of the basic cell biology and developmental programs that drive their formation during development. Recent advances in the field mean it is now possible to make hair cells in a dish from both human and mouse stem cells. However, although these cells look like hair cells and possess a number of their physiological properties, they never reach functional maturity and they don't survive long-term. HCs generated in this way also do not display the same level of functional diversity seen in a normal cochlea. It is not clear at present what goes wrong during their formation to cause these problems. Each cell type uses a different method to generate and burn energy substrates (known as their "metabolism"). These different metabolic pathways are important for regulating how cells form during development and if they are perturbed this can cause errors how the cells function during later life. In an attempt to identify novel factors that fine tune the functional properties of cochlear HCs, this project will explore how metabolism could be used as a tuneable tool with which to direct functional branch-points during their development. We will characterise the metabolic profiles of developing HCs, and determine how they change with frequency position along the cochlea. We will then explore how metabolism might be exploited to generate these functionally distinct types of sensory cell. We have already found that if metabolism is disrupted during development, HCs do not form properly. We now want to understand why this happens. Why does metabolic disruption cause these errors in normal HC development? We are addressing this novel question by investigating its role in the specification of sound frequency coding by HCs. The complex network of developmental pathways important for cochlear cell fate specification is well defined. We want to understand how metabolic and developmental signalling molecules interact during development to specify cell fate. Understanding how metabolic and developmental signalling cues regulate the basic cell biology in developing HCs has significant future impact not only for hearing loss but also any tissue such as they eye, the skin or even teeth, where there is great need to replace lost or damaged cells.

我们理解语言、听音乐或听到蚊子的高音的能力，依赖于我们内耳中高度分化的细胞——毛细胞（HCs）。这些细胞之所以如此命名，是因为它们的顶端表面有一种由一种叫做肌动蛋白的特殊蛋白质组成的毛状束。我们听到的每一个声音都是由许多不同的频率组成的。HCs的主要工作是将复杂的声音，如语音和音乐，分解成它们各自的频率成分。这个过程沿着听觉器官——耳蜗的长度进行。设想这种情况的一种方法是，把耳蜗中的hc想象成钢琴上的琴键，每个细胞或琴键对特定的频率或音符做出反应。hcc形成的发育错误或hcc的损害和丢失会导致永久性听力损失。一旦这些细胞丢失，目前还没有生物疗法可以替代它们。成功地确定产生功能可行的hcc所需的因素需要详细了解基本的细胞生物学和在发育过程中驱动其形成的发育程序。该领域的最新进展意味着现在有可能在培养皿中从人类和小鼠干细胞中制造毛细胞。然而，尽管这些细胞看起来像毛细胞，并具有许多毛细胞的生理特性，但它们永远不会达到功能成熟，也不能长期存活。以这种方式产生的hc也不显示正常耳蜗中相同水平的功能多样性。目前还不清楚在它们形成过程中出现了什么问题导致了这些问题。每种细胞类型使用不同的方法来产生和燃烧能量基质（称为它们的“新陈代谢”）。这些不同的代谢途径对于调节细胞在发育过程中如何形成很重要，如果它们受到干扰，就会导致细胞在以后的生活中如何发挥功能的错误。在试图确定微调耳蜗hc功能特性的新因素时，该项目将探索如何将代谢作为一种可调节的工具，在其发育过程中指导功能分支点。我们将描述发展中的hc的代谢特征，并确定它们如何随频率位置沿耳蜗变化。然后，我们将探索如何利用新陈代谢来产生这些功能不同的感觉细胞类型。我们已经发现，如果在发育过程中代谢被破坏，hc就不能正常形成。我们现在想知道为什么会发生这种情况。为什么代谢紊乱会导致正常HC发育中的这些错误？我们正在通过研究其在hc的声音频率编码规范中的作用来解决这个新问题。发育通路的复杂网络对耳蜗细胞命运规范很重要。我们想了解代谢和发育信号分子在发育过程中如何相互作用以指定细胞命运。了解代谢和发育信号信号如何调节hcc发展过程中的基本细胞生物学，不仅对听力损失，而且对任何组织，如眼睛、皮肤甚至牙齿，都有重大的未来影响，这些组织非常需要替换丢失或受损的细胞。