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: 2469655
• 负责人: WEI ZHENG
• 金额: $ 22.21万
• 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/2469655
• 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）环境负责人 (Pb)暴露仍然是美国的一个主要公共卫生问题。 虽然中枢神经系统（CNS）是铅的已知靶点， 毒性，发展中国家铅毒性的关键机制 大脑基本不清楚。 我们以前的工作表明，铅积累 在很大程度上，在脉络丛（CP）中，一种组织构成了 血液和脑脊液（CSF）之间的屏障。 最近我们 表明，铅在CP中的沉积与一个显着的 CSF甲状腺素运载蛋白浓度降低。 已经证明 CNS中的甲状腺素运载蛋白仅由CP产生和分泌， 主要负责将甲状腺激素输送到大脑。 它 也知道新生儿甲状腺激素缺乏会导致 不可逆转的智力迟钝 综合考虑，我们假设 环境铅暴露诱导CP TTR产生的抑制（和/或 分泌），这可能会损害大脑发育，剥夺甲状腺 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）进一步表征和研究的作用机制， 铅暴露对脑脊液TTR的影响;（2）确定脑脊液TTR下降是否导致 铅暴露导致发育中的大脑甲状腺激素缺乏; (3)为了进一步表征体外系统以研究机制， 由此Pb改变CSF和CP中的TTR和碘甲腺原氨酸。 另外我们 将探讨铅暴露是否改变了视黄醇结合的浓度， 蛋白质（RBP）和类维生素A在CSF和CP，因为RBP和TTR分泌 CP和两者都需要类维生素A运输到CNS。 本研究 应该有重大的公共卫生影响：如果铅毒性是 事实上，这与大脑中这些物质的浓度紊乱有关， 大分子，那么开发一种新的临床治疗手段， 可能 我们相信，这项研究将可能创造一个非常富有成果的 环境神经毒理学的研究途径。