ANION TRANSPORT AND LEAD NEUROTOXICITY

描述(改编自《调查者摘要》)：铅中毒是 被确定为影响最重要的环境健康危害 美国的儿童。因此，理解机制 因此，铅进入细胞可以帮助确定增加 铅暴露的风险。已知某些组织会积聚大量 铅的浓度，包括红细胞，骨骼，肾脏和 脉络丛。令人惊讶的是，据我们所知，只有一项研究涉及 红细胞摄取铅的机制，以及 提出的药理学证据表明摄取是通过调节的。 通过阴离子交换。因为，类似于红细胞、肾脏和脉络膜 神经丛上皮细胞也显示出高水平的蛋白质， 调节阴离子交换，假设铅的吸收进入 上皮细胞是通过阴离子交换来调节的。这一假设是 通过两个具体目标加以解决。第一，阴离子交换在 培养的肾上皮和脉络丛上皮对铅的摄取 并对脑血管内皮细胞进行评估。如果阴离子交换调节了 摄取铅，然后是抑制阴离子的药物和反义寡核苷酸 交易所也应该阻止铅的吸收。其次，铅的摄入量将是 在人类成纤维细胞系中进行检测，该细胞系被设计为过度表达 阴离子交换剂。由于这些电池表现出很少的阴离子交换 活性，过表达的阴离子交换应该会大大增加 铅的摄取。阴离子交换可能会受到常见疾病的影响 在接触铅的儿童中。阴离子交换也对 用来治疗这些疾病的药物。因此，这一结果 未来可能会将提案制定为毒物动力学模型 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.