Investigating the link between mitochondrial dysfunction and the integrated stress response in CNS pathology

研究中枢神经系统病理学中线粒体功能障碍与综合应激反应之间的联系

• 批准号: 2563974
• 金额: --
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 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=studentship-2563974
• 关键词: Investigating; link; between; mitochondrial; dysfunction

Mitochondria are critical for ATP provision and play other essential roles in cells such as buffering calcium and lipid synthesis (Devine & Kittler, 2018). The tight regulation of mitochondrial transport, distribution and turnover are crucial for neuronal health and disruption of mitochondrial dynamics leading to cellular stress is increasingly implicated in CNS disroders. But we still know very little about the underlying mechanisms by which damaged mitochondria lead to neuronal death. Recently, evidence suggests that disruption of mitochondrial homeostasis can lead to ISR activation. But how mitochondrial dysfunction is sensed to trigger the ISR in neurons, whether this activation contributes to neuronal pathology and if cross-talk between these two pathways can be therapeutically targeted remains a major open question. The central aim of this project is to further elucidate the mechanisms by which damaged mitochondria activate a pathological ISR in neurons. We will leverage the expertise in mitochondrial biology and mouse models of mitochondrial pathology in the Kittler lab along with expertise and tool ISR inhibitor compounds from the Crowther group at AstraZeneca. Using this approach we will be uniquely placed to further explore cross-talk between pathological mitochondrial dynamics and ISR activation with the aim of achieving the following key objectives:1) to identify the key signalling mechansims and stress-sensing proteases, chaperones and kinases through which mitochondrial damage leads to ISR activation;2) to determine which disease specific forms of mitochondrial damage can activate the ISR (e.g. altered fission/fusion, disrupted trafficking, altered mitophagy).3) to determine if blocking ISR activation leads to neuronal protection from mitochondrial insults in vitro and in vivo.

线粒体对ATP的供应至关重要，并在细胞中发挥其他基本作用，如缓冲钙和脂质合成(Devine&Kittler，2018)。线粒体运输、分布和周转的严密调控对神经元的健康至关重要，导致细胞应激的线粒体动力学中断越来越多地与中枢神经系统疾病有关。但我们仍然对线粒体受损导致神经元死亡的潜在机制知之甚少。最近，有证据表明，线粒体动态平衡的破坏可以导致ISR的激活。但线粒体功能障碍是如何在神经元中触发ISR的，这种激活是否有助于神经元病理，以及这两条通路之间的串扰是否可以作为治疗靶点，仍然是一个主要的悬而未决的问题。该项目的中心目标是进一步阐明损伤的线粒体激活神经元中病理性ISR的机制。我们将利用Kittler实验室在线粒体生物学和小鼠线粒体病理模型方面的专业知识，以及阿斯利康Crowther集团的ISR抑制剂化合物的专业知识和工具。利用这一方法，我们将独一无二地进一步探索病理线粒体动力学和ISR激活之间的相互作用，目的是实现以下关键目标：1)确定线粒体损伤导致ISR激活的关键信号机制和应激敏感蛋白水解酶、伴侣和激酶；2)确定哪些疾病特定形式的线粒体损伤可以激活ISR(例如，改变的分裂/融合、中断的运输、改变的有丝分裂)。3)确定阻断ISR激活是否在体外和体内导致神经元免受线粒体损伤的保护。