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

由于复杂的遗传基础和对遗传对细胞生物学影响的了解不足，寻找精神分裂症和相关疾病亟需的新疗法的工作一直受到阻碍。这个项目将使用新的方法来研究大脑发育过程中的细胞生物学，并利用DNA测序方面的最新发现，这些发现揭示了一组基因变异，这些变异大大增加了精神分裂症的风险。这种创新的方法将导致更好地理解精神分裂症遗传风险背后的生物学，在大脑中，它们在哪里相关，以及在生命周期中，这些基因变异何时产生最大影响。这些方法还将能够精确定位与新疗法的靶向最相关的细胞类型。我研究的一个主要目的是调查高危基因变异对突触功能的影响。突触蛋白是由细胞体内的遗传物质或突触本身的局部遗传物质合成的。在我自己的研究的支持下，越来越多的证据表明，导致精神分裂症风险的基因变异对突触合成的蛋白质产生了更大的影响。该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，并比较它们的影响。这些基因，缩写为TRIO和GRIN2A，都已知对神经元突触的功能有贡献，但尚不清楚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。为了对药物开发最有用，遗传变异的生物效应之间的汇聚点需要根据基因活动的模式进行优化，基因活动模式因个体的年龄或大脑中的特定位置而异。从以前的工作中，我们知道TRIO在一生中都很活跃，在发育早期达到顶峰，而GRIN2A在出生前不那么活跃，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会在不同的发育阶段产生不同的影响，并最终可能在不同的时间导致精神分裂症的风险。我将通过重复分析大脑发育不同时期TRIO和GRIN2A功能受损的模型中的突触蛋白合成来研究这一点，每次都比较它们的影响。埃克塞特大学提供了对单个细胞中的基因活动进行测序的新技术，这将使我能够研究影响精神分裂症风险的基因变异在大脑中的哪里会导致破坏，并细化它们对特定分子系统的影响。总之，这项研究推动了精神病学遗传学领域的新发现和新技术，将精神分裂症的复杂遗传结构浓缩为集中的易损性区域。通过确定风险变量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.