CHOROID PLEXUS AS A TARGET IN LEAD INDUCED NEUROTOXICITY

脉络丛作为铅引起的神经毒性的靶点

• 批准号: 2882844
• 负责人: WEI ZHENG
• 金额: $ 21.19万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-03-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2882844
• 关键词: biological transport; choroid plexus; developmental neurobiology; environmental toxicology; hormone regulation /control mechanism; laboratory rat; lead poisoning; neurotoxicology; neurotoxins; pituitary thyroid axis; retinoid binding proteins; retinoids; thyroid function; thyroid hormone binding protein; thyronines

DESCRIPTION: (Adapted from the Investigator's Abstract) Environmental lead (Pb) exposure remains a major public health issue in the United States. Although the central nervous system (CNS) is the known target for Pb toxicity, the crucial mechanism(s) underlying Pb toxicity in developing brain is largely unclear. Our previous work indicates that Pb accumulates to a great extent in the choroid plexus (CP), a tissue constituting a barrier between blood and cerebrospinal fluid (CSF). Recently, we demonstrated that deposition of Pb in CP is associated with a significant decrease in CSF transthyretin concentration. It has been demonstrated that transthyretin in the CNS is solely manufactured and secreted by the CP and is primarily responsible for transport of thyroid hormones to the brain. It is also known that neonatal thyroid hormone deficiency could result in irreversible mental retardation. Taken together, we hypothesize that environmental Pb exposure induces a depression of CP TTR production (and/or secretion), which may impaired brain development by depriving it of thyroid hormones. The overall goals of our research proposal are to explore the role of the blood -CSF barrier in Pb-induced neurotoxicity. Our specific aims are to: (1) further characterize the effect and study the mechanism of Pb exposure on CSF TTR; (2) to determine whether decline in CSF TTR caused by Pb exposure leads to thyroid hormone deficiency in developing brain; and (3) to further characterize an in vitro system to investigate the mechanism whereby Pb alters TTR and iodothyronines in CSF and CP. In addition, we will explore if Pb exposure alters the concentrations of retinol binding protein (RBP) and retinoids in CSF and CP because RBP and TTR are secreted by CP and both are required for retinoid transport to CNS. This research should have significant public health implications: if Pb toxicity is indeed associated with the disturbance of brain concentrations of these macromolecules, then development of a new means of clinical therapy is possible. We believe that this study will likely create a highly fruitful avenue of research in environmental neurotoxicology.

描述：（改编自研究者摘要）环境铅 (Pb) 暴露仍然是美国的一个主要公共卫生问题。 尽管中枢神经系统 (CNS) 是 Pb 的已知目标 毒性，铅在发育过程中的毒性的关键机制 大脑很大程度上不清楚。 我们之前的工作表明 Pb 会积累 在很大程度上位于脉络丛（CP）中，脉络丛是构成脉络丛的组织。 血液和脑脊液（CSF）之间的屏障。 最近，我们 表明 CP 中 Pb 的沉积与显着的 脑脊液运甲状腺素蛋白浓度降低。 已经证明 CNS 中的转甲状腺素蛋白仅由 CP 制造和分泌， 主要负责将甲状腺激素转运至大脑。 它 还已知新生儿甲状腺激素缺乏可能导致 不可逆转的精神发育迟滞。 综合起来，我们假设 环境铅暴露会导致 CP TTR 产生的抑制（和/或 分泌），这可能会通过剥夺甲状腺来损害大脑发育 荷尔蒙。 我们研究计划的总体目标是探索 血脑脊液屏障在铅诱导的神经毒性中的作用。 我们的具体 目的是：（1）进一步表征效果并研究其机制 CSF TTR 上的 Pb 暴露； (2)判断是否引起CSF TTR下降 铅暴露会导致大脑发育中甲状腺激素缺乏；和 (3) 进一步表征体外系统以研究其机制 Pb 会改变 CSF 和 CP 中的 TTR 和碘甲状腺原氨酸。 此外，我们 将探讨铅暴露是否会改变视黄醇结合的浓度 CSF 和 CP 中的蛋白质 (RBP) 和类维生素A，因为 RBP 和 TTR 是分泌的 CP 和两者都是类视黄醇转运至 CNS 所必需的。 这项研究 应该对公共健康产生重大影响：如果铅的毒性是 确实与这些物质的大脑浓度紊乱有关 大分子，那么开发新的临床治疗手段就是 可能的。 我们相信这项研究可能会创造出卓有成效的成果 环境神经毒理学的研究方向。