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

早期接触颗粒物(PM)可能会导致神经元缺陷。目前尚不清楚PM是否直接负责，或者更确切地说，是激发神经系统对其他环境挑战做出负面反应。一种提出的发病机制是神经炎症，由小胶质细胞介导，但我们受到宫内实时成像的阻碍，无法证明这一点或确定是否需要额外的应激反应。此外，我们缺乏对PM如何影响发育中神经系统的基因转录的了解，这可能导致终生神经损伤。在这个项目中，我们将使用发育中的斑马鱼胚胎模型以及人类fMRI和dMRI数据集来研究这些问题。我们将检验这样一种假设，即PM直接激活小胶质细胞导致神经炎症，但需要额外的应激源才能导致神经发育缺陷。我们将使用以下目标来验证这一假说：目标1：环境应激对脑发育(RVC)的附加影响在PM存在或不存在附加应激源(皮质醇/脂多糖)的情况下，斑马鱼胚胎/仔鱼将被提高。将对存活、形态和行为的结果进行评估。目的：利用PM介导的应激表型(RVC)的细胞成分免疫组织化学和/或转基因细胞系来分析小胶质细胞和神经元对其表型的相对贡献。目标3：对PM暴露胚胎的PM(RVC)RNA序列影响的转录分析将被分析，以确定哪些神经发育途径受到影响，以及额外的应激源是否改变了翻译谱。目的：PM暴露对婴儿神经发育的影响将使用发育中人类连接组项目中登记的婴儿的fMRI和dMRI数据集进行神经炎症分析。定量连接措施将被纳入到包含污染、遗传、临床和人口学数据的统计模型中。

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.