The genetic architecture and functional role of the mitochondrial transcriptome in the Human Brain

线粒体是许多基本细胞过程的关键，包括细胞能量产生和细胞死亡。线粒体在不同类型的细胞中执行不同的任务，但人们普遍认为，在脑和心脏等能量需求更高的组织中，线粒体的作用变得更加重要。在大脑中，线粒体需要根据不断变化的需求动态地改变其形式和功能，它们是突触信号和轴突再生的关键参与者。越来越多的证据表明，线粒体过程的功能障碍是许多神经疾病的关键，这突显了它们在大脑中的重要性。因此，了解线粒体过程在大脑中是如何调控的，以及这种调控是否在不同类型的细胞中有所不同是至关重要的。这个项目的第一个目标是整合复杂的遗传、转录和单细胞数据，以识别大脑和细胞类型对关键线粒体过程的特定调控，这些过程影响大量人类个体的下游功能(如转录、RNA修饰和定位)。这将涉及到使用计算方法来考虑核基因组和线粒体基因组之间的关系如何在大脑中变化。该项目的第二个目标将是通过对PSC来源的神经元和星形胶质细胞模型的遗传操作，确定调节这些过程对线粒体功能的下游影响。最后，将考虑这些结果在衰老过程和一系列神经疾病中的重要性。这两位主管的互补技能将加强该项目，他们将在每个领域提供支持：霍奇金森博士是线粒体过程计算分析方面的专家，而迪瓦恩博士是将IPSCs用作功能模型系统并了解线粒体在神经元和神经退行性疾病中的作用的专家。

Mitochondria are key to many fundamental cellular processes, including cellular energyproduction and cell death. Mitochondria perform different tasks in varied cell types, but it isgenerally understood that the role of mitochondria becomes even more important in tissueswith higher energy demand such as the brain and heart. In the brain, mitochondria arerequired to dynamically change their form and function in response to fluctuating demands,and they are key players in the modulation of synaptic signalling and neurite regeneration.Their importance in the brain is underscored by the accumulating evidence that thedysfunction of mitochondrial processes is key to many neurological disorders. As such, it isvital to understand how mitochondrial processes are regulated in the brain and whether thisvaries across different cell types.The first objective of this project is to integrate complex genetic, transcriptomic and singlecelldata to identify brain and cell-type specific regulation of key mitochondrial processes thatinfluence downstream function (such as transcription, RNA modification and localisation)across a large number of human individuals. This will involve using computational methods toconsider how relationships between the nuclear and mitochondrial genomes vary across thebrain. The second objective of the project will be to identify the downstream consequences ofmodulating these processes on mitochondrial function, through the genetic manipulation ofiPSC-derived neuronal and astrocyte cell models. Finally, these results will then be consideredfor their importance in ageing processes and a range of neurological disorders.The project will be strengthened by the complementary skills sets of the two supervisors,who will provide support in each area: Dr Hodgkinson is an expert in the computationalanalysis of mitochondrial processes, whereas Dr Devine is an expert in using iPSCs asfunctional model systems and understanding the roles of mitochondria in neurons andneurodegenerative diseases.