Investigating polyamines as a treatment target for mitochondrial disease

研究多胺作为线粒体疾病的治疗靶点

• 批准号: MR/V013130/1
• 负责人: Joseph Bateman
• 金额: $ 71.25万
• 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=MR%2FV013130%2F1
• 关键词: Investigating; polyamines; treatment; target; mitochondrial

Mitochondrial diseases are a group of genetic disorders that cause damage to cells and tissues in the body and affect up to 1 in 4300 people in the UK. There are currently no licenced treatments and developing therapeutic strategies for mitochondrial diseases has been highlighted as a priority area. Mitochondria are tiny structures within cells, which play a critical role in cellular energy production and metabolism. When these 'powerhouses' malfunction, it can result in chronic illness. Organs with high metabolic demands are often the most severely affected and mitochondrial diseases frequently cause damage to the nervous system. Extensive evidence from animal and clinical studies also suggests that defective mitochondria play a critical role in other neurodegenerative diseases, including Alzheimer's and Parkinson's disease. In this project we will study how defective mitochondria trigger changes in the expression of key metabolic genes and how this causes neurodegeneration. We hypothesise that changes in the levels of metabolites called polyamines in the brain contribute to neurodegeneration in mitochondrial disease.We will test this hypothesis using fruit flies and mice that have been given the mitochondrial disease Leigh syndrome, which causes neurodegeneration and death in children. We will use these 'disease models' to better understand the cause of the disease and identify new treatments. The fly model is fast and inexpensive to study, while the mouse model more closely mirrors human mitochondrial disease. Using highly sensitive techniques, we will measure how mitochondria cause changes in polyamine metabolite levels in the brain in this fly model of Leigh syndrome. Using cutting-edge genetic technology, we will study the role of key metabolic genes that are switched on or off at the wrong time in nerve cells in the fly model, to discover how they contribute to nerve cell damage. We will also test whether blocking key metabolic genes, or treatment with a metabolite called spermidine, can prevent damage to the nervous system. Overall, this project will lead to a new understanding of the cause of mitochondrial disease and novel strategies to treat the disease in patients. In the long-term the project will also contribute to the understanding and treatment of other neurodegenerative diseases such as Alzheimer's and Parkinson's disease.

线粒体疾病是一组遗传性疾病，会导致体内细胞和组织受损，在英国每4300人中就有1人受到影响。目前还没有获得许可的治疗方法，开发线粒体疾病的治疗策略已被列为优先领域。线粒体是细胞内的微小结构，在细胞能量产生和代谢中起着关键作用。当这些“能量源”发生故障时，可能会导致慢性疾病。具有高代谢需求的器官通常受到最严重的影响，线粒体疾病经常对神经系统造成损害。来自动物和临床研究的大量证据也表明，有缺陷的线粒体在其他神经退行性疾病中起着关键作用，包括阿尔茨海默病和帕金森病。在这个项目中，我们将研究缺陷线粒体如何触发关键代谢基因表达的变化，以及这如何导致神经退行性变。我们假设大脑中称为多胺的代谢物水平的变化有助于线粒体疾病中的神经变性。我们将使用患有线粒体疾病Leigh综合征的果蝇和小鼠来验证这一假设，该疾病导致儿童神经变性和死亡。我们将使用这些“疾病模型”来更好地了解疾病的原因并确定新的治疗方法。苍蝇模型研究起来快速且便宜，而小鼠模型更接近于人类线粒体疾病。使用高灵敏度的技术，我们将测量线粒体如何引起多胺代谢物水平的变化，在这个苍蝇模型的利综合征的大脑。利用尖端的遗传技术，我们将研究在果蝇模型中神经细胞中在错误的时间打开或关闭的关键代谢基因的作用，以发现它们如何导致神经细胞损伤。我们还将测试阻断关键代谢基因或用一种叫做亚精胺的代谢物治疗是否可以防止对神经系统的损害。总的来说，该项目将导致对线粒体疾病原因的新理解和治疗患者疾病的新策略。从长远来看，该项目还将有助于了解和治疗其他神经退行性疾病，如阿尔茨海默病和帕金森病。

项目成果

A Drosophila model of mitochondrial disease phenotypic heterogeneity

线粒体疾病表型异质性的果蝇模型

• DOI: 10.1101/2023.12.05.570102
• 发表时间: 2023
• 作者: Granat L

Mitochondrial DNA Transport in Drosophila Neurons.

果蝇神经元中的线粒体 DNA 运输。

• DOI: 10.1007/978-1-0716-1990-2_21
• 发表时间: 2022
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Bateman JM

Yeast NDI1 reconfigures neuronal metabolism and prevents the unfolded protein response in mitochondrial complex I deficiency.

• DOI: 10.1371/journal.pgen.1010793
• 发表时间: 2023-07
• 期刊: PLoS genetics
• 影响因子: 4.5