SPP1, Oxidative Stress, and Lead Toxicity

项目摘要 SPP 1、氧化应激和铅毒性 铅（Pb）是一种广泛存在的环境毒物，在脑发育的早期阶段， 发育对神经认知功能具有长期影响。然而，分子 早期大脑发育对铅的独特易感性的机制仍然很差 明白神经干细胞（Neural Stem Cells，NSCs）作为中枢神经系统的祖细胞， 在塑造发育中的大脑中起着重要作用。我们进行了全局转录谱分析 并鉴定了神经干中铅处理显著改变其表达的基因 细胞大多数Pb上调的基因是主转录因子NRF2的靶基因 氧化应激反应，包括SPP1（分泌磷蛋白1）。SPP1已知 为了具有神经保护作用，并且与此一致，我们证明了添加重组 SPP1蛋白可降低铅对神经干细胞生长的抑制作用。使用现有数据 环境流行病学队列的全基因组关联研究，我们进一步 表明SPP 1启动子区的遗传变异与 改善儿童的认知发展。基于这些研究，我们假设， NRF2介导的SPP 1上调作为减少铅的自我保护反应发挥作用 神经干细胞损伤的研究进展我们进一步假设， 铅暴露后SPP1上调能力受损，导致神经干细胞 细胞功能障碍，从而损害早期脑发育。测试这些 假设，我们提出了一个高度整合的项目，结合分子机制， 在培养的神经干细胞、体内小鼠模型和人类遗传流行病学方面的研究， 儿童接触铅目的1探讨SPP1在细胞内的作用机制 上调可保护神经干细胞免受铅毒性。目标2将研究 SPP1介导铅对小鼠神经发育的影响目标3将决定 SPP1变异体与铅暴露儿童神经发育的功能相关性 这项研究的结果将建立SPP 1上调作为一个关键机制，连接铅 暴露与神经干细胞功能和神经发育的儿童，并可能确定 SPP1作为预防和治疗有害生物的新靶点 儿童铅暴露对神经发育的影响。

PROJECT SUMMARY SPP1, Oxidative Stress, and Lead Toxicity Exposure to lead (Pb), a pervasive environmental toxicant, at the early stages of brain development has long-lasting effects on neurocognitive function. However, the molecular mechanisms underlying the unique susceptibility of early brain development to Pb remain poorly understood. As the progenitor cells in the central nervous system, neural stem cells (NSCs) play an essential role in shaping the developing brain. We performed global transcriptional profiling and identified genes whose expression is significantly altered by Pb treatment in neural stem cells. Most of the Pb-upregulated genes are targets of NRF2—the master transcriptional factor for the oxidative stress response, including SPP1 (secreted phosphoprotein 1). SPP1 is known to be neuroprotective, and consistent with this, we demonstrated that addition of recombinant SPP1 protein reduces the inhibitory effect of Pb on NSC growth. Using data from existing genome-wide association studies of an environmental epidemiological cohort, we further showed that a genetic variant in the promoter region of SPP1 significantly associates with improved cognitive development in children. Based on these studies, we hypothesize that NRF2-mediated SPP1 upregulation functions as a self-protective response to reduce Pb exposure-induced injury in neural stem cells. We further hypothesize that failure or compromised ability to upregulate SPP1 in response to Pb exposure contributes to neural stem cell dysfunction and consequently the impairment of early brain development. To test these hypotheses, we propose a highly integrative project that combines molecular mechanistic studies in cultured neural stem cells, in vivo mouse models, and human genetic epidemiology in children exposed to Pb. Aim 1 will investigate the mechanisms thorough which SPP1 upregulation protects against Pb toxicity in neural stem cells. Aim 2 will investigate the role of SPP1 in mediating the effect of Pb on neurodevelopment in mice. Aim 3 will determine the functional association of SPP1 variants with neurodevelopment in children exposed to Pb. Results from this study will establish SPP1 upregulation as a critical mechanism linking Pb exposure with neural stem cell function and neurodevelopment in children, and may identify SPP1 as a novel target for preventative and therapeutic interventions against detrimental neurodevelopment effects of Pb exposure in children.