CHOROID PLEXUS AS A TARGET IN LEAD INDUCED NEUROTOXICITY

描述：(改编自《调查者摘要》)环境铅 (PB)暴露在美国仍然是一个主要的公共卫生问题。 虽然中枢神经系统(CNS)是铅的已知靶点 发育中铅中毒的关键机制--毒性(S) 大脑在很大程度上是不清楚的。我们以前的工作表明，铅积累 在很大程度上，在脉络丛(CP)中，构成 血和脑脊液(CSF)之间的屏障。最近，我们 证明了铅在CP中的沉积与显著的 脑脊液中转甲状腺素浓度降低。事实证明， 中枢神经系统中的转甲状腺素仅由CP制造和分泌 主要负责将甲状腺激素输送到大脑。它 也已知新生儿甲状腺激素缺乏会导致 不可逆转的智力低下。总而言之，我们假设 环境铅暴露导致Cp Ttr产生抑制(和/或 分泌)，这可能会剥夺大脑的甲状腺，从而损害大脑的发育 荷尔蒙。我们研究提案的总体目标是探索 血脑脊液屏障在铅中毒中的作用我们的特定 目的是：(1)进一步表征和研究其作用机制 脑脊液TTR铅暴露；(2)确定脑脊液TTR值的下降是否导致 铅暴露导致发育中的大脑甲状腺激素缺乏； (3)进一步鉴定体外系统以研究其作用机制。 从而改变脑脊液和脑脊液中的TTR值和碘甲腺原氨酸。此外，我们 将探索铅暴露是否会改变视黄醇结合浓度 脑脊液和脑脊液中的蛋白质(RBP)和维甲酸类化合物，因为RBP和TTR是分泌的 两者都是维甲酸转运到中枢神经系统所必需的。这项研究 应该会对公众健康产生重大影响：如果铅中毒 确实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 有可能。我们相信，这项研究很可能会创造一个非常富有成果的 环境神经毒理学研究大道。

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.