Something in the air - investigating the impact of air pollution on neurodevelopment in the zebrafish model.

生命早期暴露于颗粒物（PM）可能导致神经元缺陷。目前尚不清楚PM是否直接负责，或者更确切地说，是启动神经系统对其他环境挑战做出不利反应。一种被提出的机制是由小胶质细胞介导的神经炎症，但由于缺乏实时子宫内成像来证明这一点或确定是否需要额外的应激源，我们受到了阻碍。此外，我们缺乏对PM如何影响发育中的神经系统基因转录的理解，这可能导致终身神经损伤。在这个项目中，我们将使用发展中的斑马鱼胚胎模型和人类fMRI和dMRI数据集来研究这些问题。我们将验证PM激活小胶质细胞直接导致神经炎症的假设，但需要额外的压力源来诱导神经发育缺陷。我们将使用以下目标来验证这一假设：目标1：环境应激对大脑发育的累加性影响（RVC）斑马鱼胚胎/幼虫将在PM存在或不存在额外应激源（皮质醇/LPS）的情况下饲养。将评估存活、形态和行为的结果。免疫组织化学和/或转基因细胞系将用于解剖小胶质细胞和神经元对表型的相对贡献。细胞生物能量学，代谢通量，信号传导和细胞死亡也将被检查。目的3：转录组学分析受PM （RVC）影响的途径，将分析PM暴露胚胎的rnaseqprofile，以确定哪些神经发育途径受到影响，以及是否有额外的应激源改变转录谱。目的4：暴露于PM对中期出生婴儿（KCL）神经发育的影响神经炎症分析将使用发育中的人类连接组项目中登记的婴儿的fMRI和dmri数据集进行。定量连接组测量将与污染、遗传、临床和人口统计数据一起纳入统计模型。

Early-life exposure to particulate matter (PM) may cause neuronal deficits. It is notknown whether PM is directly responsible or rather primes the nervous system torespond adversely to other environmental challenges. One proposed mechanism ofaction is neuroinflammation, mediated by microglial cells, but we are hampered bylack of real-time in utero imaging to prove this or identify whether additional stressorsare required. Additionally, we lack understanding of how PM impacts upon genetranscription in the developing nervous system, which may contribute to life-longneurological impairment. In this project, we will used both the developing zebrafishembryo model and human fMRI and dMRI datasets to investigate these questions. Wewill test the hypothesis that PM activates microglial cells directly resulting inneuroinflammation but that additional stressors are required to induceneurodevelopmental deficits. We will test this hypothesis using the followingobjectives: Objective 1: Additive impacts of environmental stress on braindevelopment (RVC) Zebrafish embryos/larvae will be raised in the presence of PM withor without additional stressors (cortisol/LPS). Outputs of survival, morphology andbehaviour will be evaluated. Objective 2: Cellular contribution to PM-mediated stressphenotypes (RVC) Immunohistochemistry and/or transgenic lines will be used todissect relative contributions of microglia and neurons to the phenotype. Cellularbioenergetics, metabolic flux, signalling and cell death will also be examined.Objective 3: Transcriptomic analysis of pathways impacted by PM (RVC) RNAseqprofiles of PM exposed embryos will be analysed to determine whichneurodevelopmental pathways are impacted and if additional stressors change thetranscription profile. Objective 4: Impact of exposure to PM on neurodevelopment interm born infants (KCL) Neuroinflamation analyses will be performed using fMRI anddMRI datasets from infants enrolled in the Developing Human Connectome project.Quantitative connectomic measures will be incorporated into statistical models withpollution, genetic, clinical and demographic data.