Understanding tubulin regulation during neuronal development, ageing and degeneration

了解神经元发育、衰老和退化过程中微管蛋白的调节

• 批准号: 2110398
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2110398
• 关键词: Understanding; tubulin; regulation; during; neuronal

Axons are slender, up-to-a-meter long, cable-like extensions of neurons which form the nerves and nerve tracts that wire our bodies and brain. These delicate cellular structures have to be maintained for an organism's life time and are often the first to be affected in ageing, injury and neurodegeneration. To understand such conditions and identify ways to improve axon maintenance and regeneration, we study the regulation of microtubules (MTs) which form parallel bundles running all along axons to form their structural backbones and life-sustaining transport highways. On this project, you will study MT polymerisation which is the key driver of MT bundle formation and of continuous MT turn-over that protects axonal bundles from senescence during ageing. You will focus on the problem of how tubulins (i.e. the building blocks of MTs) are made available and continuously supplied in the narrow axons, up to a meter away from the cell body. This fascinating topic is most relevant to axon biology and pathology but surprisingly little understood. Your pioneering work will be based on our recently published mechanistic model of axonal tubulin supply and MT polymerisation, deduced from our own data and general knowledge in the field [Ref.1]. You will use cutting edge methodologies to study (1) contributions made by axonal transport and local tubulin translation, (2) roles of the chaperone machinery of tubulin assembly, and (3) mechanisms of tubulin storage and gene expression regulation. For your studies, you will use neurons of the fruit fly Drosophila, which provides uniquely powerful genetic and cell biological means in order to efficiently generate new understanding that can then be applied to higher animals [Ref.2]. You will be able to capitalise on expertises of the host group (AP) on MT regulation and the Drosophila neuron model, of the first co-supervisor's group (TW) on high resolution imaging and quantitative approaches [Ref.3,4], and of the second co-supervisor's group (MA) on RNA visualisation and processing [Ref.5]. Your transferable, experimental skill training opportunities will include genetics, cell biology, molecular biology, imaging techniques (live, high resolution, axonal transport, spatial detection of RNA and translational activity), quantitative analyses and modelling, as well as expertise in the important research areas of cytoskeleton and neurobiology. Finally, AP is an expert in science communication [Ref.6] providing further training opportunities important for your future career.

轴突是细长的，长达一米，是神经元的索状延伸，它构成了连接我们身体和大脑的神经和神经束。这些精致的细胞结构必须在生物体的整个生命周期中得到维持，而且往往是衰老、受伤和神经退化的第一个受害者。为了了解这些情况并确定改善轴突维持和再生的方法，我们研究了微管（MTs）的调控，这些微管形成平行束，沿着轴突运行，形成其结构骨干和维持生命的运输公路。在这个项目中，你将学习MT聚合，这是MT束形成的关键驱动因素，以及在衰老过程中保护轴突束免受衰老的MT连续翻转。你将专注于小管（即mt的构建块）是如何在距离细胞体一米远的狭窄轴突中获得和持续供应的问题。这个引人入胜的话题与轴突生物学和病理学最相关，但令人惊讶的是，人们对它知之甚少。您的开创性工作将基于我们最近发表的轴突微管蛋白供应和MT聚合的机制模型，从我们自己的数据和该领域的一般知识中推断出来[参考文献1]。您将使用尖端的方法来研究(1)轴突运输和局部微管蛋白翻译的贡献，(2)微管蛋白组装的伴侣机制的作用，以及(3)微管蛋白储存和基因表达调控的机制。在您的研究中，您将使用果蝇的神经元，它提供了独特的强大的遗传和细胞生物学手段，以便有效地产生新的理解，然后可以应用于高等动物[参考文献2]。您将能够利用主小组（AP）在MT调节和果蝇神经元模型方面的专业知识，第一联合主管小组（TW）在高分辨率成像和定量方法方面的专业知识[参考文献3,4]，以及第二联合主管小组（MA）在RNA可视化和处理方面的专业知识[参考文献5]。您可转移的实验技能培训机会将包括遗传学，细胞生物学，分子生物学，成像技术（实时，高分辨率，轴突运输，RNA空间检测和翻译活性），定量分析和建模，以及细胞骨架和神经生物学等重要研究领域的专业知识。最后，AP是科学传播方面的专家[Ref.6]，为您未来的职业生涯提供了重要的进一步培训机会。