Partitioning the effects of schizophrenia risk variants on dynamics of the local synaptic translatome in cortex

寻找精神分裂症和相关疾病急需的新疗法一直受到复杂的潜在遗传学和对细胞生物学遗传效应的理解不足的阻碍。该项目将使用新的方法研究大脑发育过程中的细胞生物学，并利用DNA测序中的最新发现，这些发现揭示了一系列遗传变异，这些变异大大增加了精神分裂症的风险。这种创新的方法将使人们更好地了解精神分裂症遗传风险背后的生物学，以及它们在大脑中的相关位置，以及在生命周期中这些遗传变异的影响最大。这些方法还将能够精确定位与新疗法靶向最相关的细胞类型。我研究的主要目的是调查高风险遗传变异对突触功能的影响。突触蛋白质是由遗传物质在细胞体内或在突触本身局部合成的。越来越多的证据表明，导致精神分裂症风险的遗传变异对突触合成的蛋白质产生了更大的影响，这一点得到了我自己研究的支持。本项目将重点研究与精神分裂症相关的两种基因变异模型中蛋白质的突触合成，并比较它们的效果。这些基因，缩写为TRIO和GRIN2A，都已知有助于神经元突触的功能，但不知道这些基因的改变是否会影响局部蛋白质合成，或者它们如何影响突触的脆弱性。为了最大限度地用于药物开发，遗传变异的生物学效应之间的趋同点需要根据基因活性模式进行改进，这些模式根据个体的年龄或大脑中的特定位置而变化。从以前的工作中，我们知道TRIO在整个生命中都很活跃，在早期发育期间达到顶峰，而GRIN2A在出生前活性要低得多，从出生到青春期变得越来越活跃。因此，这些基因的改变可能在不同的发育阶段产生不同的影响，并最终导致精神分裂症在不同时期的风险。我将通过在大脑发育的不同时期重复分析TRIO和GRIN2A功能受损模型中的突触蛋白合成来研究这一点，每次比较它们的效果。埃克塞特大学（University of Exeter）提供的对单个细胞中基因活性进行测序的新技术，将使我能够研究大脑中影响精神分裂症风险的遗传变异在哪里造成破坏，并改善它们对特定分子系统的影响。总之，这项研究推动了精神遗传学领域的新发现和新技术，将精神分裂症复杂的遗传结构浓缩为集中的脆弱性。通过确定风险变异在何时何地影响突触基因的活性，我们可以为精神分裂症和相关疾病提供更有针对性和更有效的治疗策略。

The search for much-needed new treatments for schizophrenia and related disorders has been hampered by complex underlying genetics and a poor understanding of the genetic effects on cell biology. This project will use novel methods for studying cell biology during brain development and exploit recent discoveries in DNA sequencing that have revealed a subset of genetic variants that substantially increase the risk of schizophrenia. This innovative approach will lead to a better understanding of the biology behind the genetic risks of schizophrenia, where in the brain they are relevant and when during the lifespan these genetic variants have the most impact. These methods will also enable the pinpointing of cell types most relevant for the targeting of novel therapies. A primary aim of my research will be to investigate the effects of high-risk genetic variants on the function of synapses. Synaptic proteins are synthesised from genetic material either within the cell body or locally at the synapses themselves. There is growing evidence, supported by my own research, that genetic variants contributing to the risk of schizophrenia exert greater impact on proteins synthesised at synapses. This project will focus on the synaptic synthesis of proteins in two models of gene variation associated with schizophrenia and compare their effects. These genes, abbreviated to TRIO and GRIN2A, are both known to contribute to the function of neuronal synapses, but it is not known whether alteration of these genes affects local protein synthesis, or how they influence vulnerability at the synapse. To be of most use to drug development, points of convergence among the biological effects of genetic variants need refining based on patterns of gene activity, which vary based on the age of the individual or the particular location in the brain. From previous work, we know that TRIO is active throughout life, peaking during early development, whilst GRIN2A is much less active before birth and becomes increasingly active from birth until adolescence. Therefore, alterations in these genes may have different effects at different stages of development and could ultimately contribute to the risk of schizophrenia at different times. I will investigate this by repeating analyses of synaptic protein synthesis in models of disrupted TRIO and GRIN2A function at different periods of brain development, each time comparing their effects. New technologies for sequencing gene activity in individual cells, available at the University of Exeter, will enable me to study where in the brain genetic variants influencing the risk of schizophrenia cause disruption and refine their effects on particular molecular systems. Together, this research takes forward new discoveries and technologies in the field of psychiatric genetics to condense the complex genetic architecture of schizophrenia into concentrated pockets of vulnerability. By defining when and where risk variants affect the activity of synaptic genes, we can facilitate much more targeted and effective treatment strategies for schizophrenia and related conditions.