SPP1, Oxidative Stress, and Lead Toxicity

项目总结 SPP1、氧化应激和铅中毒 在大脑的早期阶段暴露于铅(一种普遍存在的环境毒物) 发育对神经认知功能有长期的影响。然而，分子 早期大脑发育对铅的独特易感性的机制仍不清楚 明白了。作为中枢神经系统的祖细胞，神经干细胞(NSCs)发挥着重要作用 在塑造发育中的大脑方面起着至关重要的作用。我们进行了全球转录图谱分析 并确定了铅处理后神经干细胞中表达显著改变的基因 细胞。大多数铅上调的基因是主要转录因子NRF2的靶标 用于氧化应激反应，包括SPP1(分泌型磷蛋白1)。SPP1是已知的 为了神经保护，并与此一致，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 研究表明，SPP1启动子区域的一个遗传变异与 改善儿童的认知发展。基于这些研究，我们假设 NRF2介导的SPP1上调对铅还原的自我保护作用 暴露所致的神经干细胞损伤。我们进一步假设失败或 铅暴露导致SPP1上调的能力受损与神经干细胞有关 细胞功能障碍，从而损害早期大脑发育。为了测试这些 假设，我们提出了一个结合了分子力学的高度集成的方案 在培养神经干细胞、活体小鼠模型和人类遗传流行病学方面的研究 儿童铅暴露。目标1将深入研究SPP1 上调对神经干细胞的铅毒性具有保护作用。目标2将调查 SPP1在介导铅对小鼠神经发育影响中的作用目标3将决定 铅接触儿童SPP1变异与神经发育的功能关联 这项研究的结果将确立SPP1上调是连接铅的关键机制 暴露于儿童神经干细胞功能和神经发育，并可能识别 SPP1作为预防和治疗有害物质干预的新靶点 铅暴露对儿童神经发育的影响

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.