ANION TRANSPORT AND LEAD NEUROTOXICITY

描述（改编自研究者摘要）：铅毒性是 被确定为影响人类健康的最重要的环境危害 在美国的孩子们。 因此，理解机制 铅进入细胞的方式可以帮助决定增加 铅暴露的风险。 已知某些组织会大量积聚 铅的浓度，这些包括红细胞，骨骼，肾脏和 脉络丛 令人惊讶的是，据我们所知， 红细胞吸收铅的机制，以及 药理学证据表明，摄取是介导的 阴离子交换 因为，类似于红细胞，肾脏和脉络膜 神经丛上皮细胞也显示高水平的蛋白质， 介导阴离子交换，假设铅的摄入 上皮细胞通过阴离子交换介导。 这种假设是 通过两个具体目标来实现。 第一，阴离子交换在 培养肾上皮和脉络丛上皮对铅摄取 并对脑内皮进行评估。 如果阴离子交换介导 铅的摄取，然后是药物和反义寡核苷酸， 交换还应阻止铅的吸收。 其次，铅的摄入量将是 在人成纤维细胞系中检查，该细胞系被工程化以过表达 阴离子交换剂 由于这些细胞显示很少的阴离子交换 活性，阴离子交换的过度表达将大大增加 铅的吸收。 阴离子交换可能会受到常见疾病的影响 在儿童接触铅的情况下。 阴离子交换也对 用于治疗这些疾病的药物。 因此，由此产生的结果 该提案可能在未来制定为毒代动力学模型， 预测铅中毒的危险因素。

DESCRIPTION (Adapted from the Investigator's Abstract): Lead toxicity was identified as the most important environmental health hazard affecting children in the United States. Consequently, understanding mechanisms whereby lead enters cells can aid in determining factors that increase the risk of lead exposure. Certain tissues are known to accumulate large concentrations of lead and these include erythrocytes, bone, kidney and choroid plexus. Surprisingly, only one study, to our knowledge, addressed the mechanism responsible for lead uptake into erythrocytes, and pharmacological evidence was presented suggesting that uptake was mediated by anion exchange. Since, similar to erythrocytes, kidney and choroid plexus epithelial cells also display high levels of the protein that mediates anion exchange, it is hypothesized that the uptake of lead into epithelial cells is mediated by anion exchange. This hypothesis is addressed through two specific aims. First, the role of anion exchange in lead uptake in cultures of renal epithelium and choroid plexus epithelium and brain endothelium will be assessed. If anion exchange mediates the uptake of lead, then drugs and antisense oligonucleotides that inhibit anion exchange should also block uptake of lead. Second, lead uptake will be examined in a human fibroblast cell line that is engineered to overexpress anion exchanger. Since these cells display very little anion exchange activity, overexpression of anion exchange should greatly increase the uptake of lead. Anion exchange may be affected by ailments that are common in children who are exposed to lead. Anion exchange is also sensitive to drugs that are used to treat these disorders. Thus, the results from this proposal may in the future be formulated into a toxicokinetic model to predict risk factors for lead toxicity.