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。线粒体在不同的细胞类型中执行不同的任务，但人们普遍认为，线粒体在能量需求较高的组织（如大脑和心脏）中的作用更为重要。在大脑中，线粒体需要动态改变其形式和功能以响应波动的需求，它们在突触信号和神经突再生的调节中起着关键作用。越来越多的证据表明，线粒体过程的功能障碍是许多神经系统疾病的关键，这突显了它们在大脑中的重要性。因此，了解线粒体过程是如何在大脑中被调节的，以及这是否在不同的细胞类型中有所不同，是至关重要的。该项目的第一个目标是整合复杂的遗传、转录组学和单细胞数据，以识别影响大量人类个体下游功能（如转录、RNA修饰和定位）的关键线粒体过程的大脑和细胞类型特异性调节。这将涉及使用计算方法来考虑核和线粒体基因组之间的关系在整个大脑中是如何变化的。该项目的第二个目标将是通过对源自fipsc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后果。最后，这些结果将在衰老过程和一系列神经系统疾病中发挥重要作用。该项目将通过两位导师的互补技能得到加强，他们将在每个领域提供支持：Hodgkinson博士是线粒体过程计算分析方面的专家，而Devine博士是使用iPSCs作为功能模型系统和理解线粒体在神经元和神经退行性疾病中的作用方面的专家。

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.