Investigating the connection between cytoskeletal and mitochondrial homeostasis during ageing

研究衰老过程中细胞骨架和线粒体稳态之间的联系

• 批准号: 2888331
• 金额: --
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Studentship
• 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=studentship-2888331
• 关键词: Investigating; connection; between; cytoskeletal; mitochondrial

Project summary (maximum of 4000 characters including spaces/returns) -from original proposal Ageing is accompanied by the decline in motor, sensory and cognitive functions, all severely impacting on human health. It is of high urgency to gain a better understanding of the precise physiological processes underlying neuronal decay during ageing.Various subcellular changes reported for neurons of aged brains include alterations in their microtubule cytoskeleton, changes in mitochondrial localisation or function, inefficient auto-phagosome-lysosome systems, axonal atrophy and deterioration of synapses culminating in neuronal communication deficits. We hypothesise that these changes are not separate and there are causative links between them that follow a stepwise cascade of deterioration. Mitochondria are vital components of synapses, critical for their function by providing energy, metabolites and calcium buffers. It is therefore necessary to maintain a healthy pool of synaptic mitochondria and to ensure the clearance of damaged ones by mitophagy. Mitophagy depends on the autophagosome-lysosome system. Microtubules coordinate the organisation and function of these organelles and the removal of faulty mitochondria. The overarching aim of this work is to study whether microtubule decay can lead to organelle dysfunction and to establish whether this pathological path can explain axonal ageing. Our detailed objectives are:1 To establish the changes in mitochondrial function during neuronal ageing. 2 To investigate whether induced changes in microtubule networks mimic mitochondrial pathologies known from ageing neurons.3 To establish underlying mechanisms linking age-related microtubule perturbation and mitochondrial dysfunction such as the impairment of autophagy/mitophagy.4 To establish whether such alteration contributes to the atrophy of neurons in the ageing brain and study whether microtubules provide a novel target to improve the health of mitochondria. We will use our well-established Drosophila models of neuronal ageing in the brain in vivo and in primary neuronal cultures, as well as mammalian cell models including human cells from young and old individuals. We will study the connection between mitochondrial biology, the autophagosome and the microtubule cytoskeleton in the ageing context employing advanced imaging techniques, cellular and molecular biology, biochemistry and genetics. We aim to provide new explanations for neuronal deterioration in ageing and potential therapeutic strategies.

项目摘要（最多有4000个字符，包括空间/回报） - 从原始提案老化伴随着运动，感觉和认知功能的下降，所有这些都对人类健康都严重影响。对老年大脑神经元报道的各种细胞衰减过程中的神经元衰减的精确生理过程有更好的了解是高度紧迫的。系统，轴突萎缩和突触的恶化最终导致神经元通信缺陷。我们假设这些变化不是分开的，并且它们之间存在逐步级联恶化的原因。线粒体是突触的重要组成部分，通过提供能量，代谢物和钙缓冲液对它们的功能至关重要。因此，有必要维持健康的突触线粒体池，并确保通过线粒体清除受损的线粒体。线粒体取决于自噬体 - 赖以体形系统。微管协调了这些细胞器的组织和功能，并去除了故障的线粒体。这项工作的总体目的是研究微管衰变是否会导致细胞器功能障碍，并确定这种病理路径是否可以解释轴突衰老。我们的详细目标是：1建立神经元衰老期间线粒体功能的变化。 2要调查诱导的微管网络的变化是否模仿衰老神经元已知的线粒体病理学。3建立与年龄相关的微管扰动和线粒体功能障碍联系起来的基本机制衰老大脑中的神经元并研究微管是否提供了改善线粒体健康的新靶标。我们将在体内和原发性神经元培养物中使用良好的神经元衰老的果蝇模型，以及包括来自年轻人和老年人的人类细胞在内的哺乳动物细胞模型。我们将研究使用先进的成像技术，细胞和分子生物学，生物化学和遗传学的线粒体生物学，自噬体和微管细胞骨架之间的联系。我们旨在为衰老和潜在治疗策略的神经元恶化提供新的解释。