ADHESION AND REPULSION MOLECULES IN DEVELOPMENTAL NEUROTOXIC INJURY

描述(由申请人提供) 神经粘连的适当的时空表达和 排斥分子，膜蛋白，提供指导性指导和 对神经元和轴突运动的支持对正常大脑发育至关重要 这些分子的同步表达和功能的干扰 不良后果从轻微的学习障碍到严重的 畸形。接触有毒金属，特别是已知的甲基汞 导致发育中的行为障碍和学习能力不足 成年人的过程--可能是通过共同的扰乱大脑的机制 形态发生。据推测，神经毒性金属会扰乱大脑 通过破坏共同调节的表达和 关键的形态调节黏附和排斥分子的功能。至 要阐明这些金属的神经毒性作用，将有四个问题 在海马体和小脑进行检查：1)暴露于神经毒性金属 改变黏附分子和排斥分子在不同阶段的表达 大脑发育，从而影响形态发生？2)有选择性 转录、翻译或翻译后过程介导金属诱导 改变黏附和排斥分子？3)什么行为 毒物干扰的黏附和排斥分子的后果？4)可以 有毒金属对形态调节分子的有害影响 通过干预策略修改或改善？ 补充的形态、生化和行为评估将是 用来表征甲基汞或铅暴露对人体的不利影响 黏附分子、NCAML1、N-钙粘蛋白和排斥的Eph家族 海马体(终生保持可塑性)和小脑中的分子 (在这种情况下，可塑性消失，成熟)。对结构性和结构性的影响 行为发育将在体内解决，使用体外和体外 模特们。将评估目前针对金属毒性的临床干预措施 对分子的影响。由于数据是由暴露评估开发的 和干预和临床科学项目，其他候选神经毒性 类似地，将研究试剂对附着力的影响和 排斥力对正常发育至关重要。长期目标是 阐明有毒金属和其他外来生物物质改变的机制 神经通路的形成和突触调节及其后果 曝光率可能会降到最低。

DESCRIPTION (provided by applicant) The appropriate temporal and spatial expression of neural adhesion and repulsion molecules, membrane proteins which provide instructive guidance and support for neuron and neurite movement, is critical to normal brain develop disturbance of the synchronous expression and function of these molecules has adverse consequences ranging fro subtle learning disabilities to severe malformations. Exposure to toxic metals, particularly methylmercury known to result in behavioral disabilities in development and in deficient learning and processes in adults-possibly by the shared mechanism of disturbing brain morphogenesis. It is hypothesized that neurotoxic metals perturb brain development/morphogenesis by disrupting the co-regulated expression and function of critical morphoregulatory adhesion and repulsion molecules. To elucidate the neurotoxic roles of these metals, four questions will be examined in hippocampus and cerebellum: 1) Does exposure to neurotoxic metals alter the expression of adhesion and repulsion molecules during stages of brain development, and thereby compromise morphogenesis? 2) Do selective transcriptional, translational or posttranslational processes mediate metal-induced changes adhesion and repulsion molecules? 3) What are the behavioral consequences of toxicant-disturbed adhesion and repulsion molecules? 4)Can the deleterious effects of toxic metals on morphoregulatory molecules be modified or ameliorated by intervention strategies? Complementary morphological, biochemical and behavioral assessments will be used to characterize the adverse of methylmercury or lead exposure on the adhesion molecules, NCAM L1, N-cadherin, and the Eph family of repulsion molecules in hippocampus (which remain plastic throughout life)and cerebellum (in which plasticity fades maturation). Consequences to both structural and behavioral development will be addressed in vivo, using ex vivo and in vitro models. Current clinical interventions for metal toxicity will be assessed for effects on molecules. As data are developed by the Exposure Assessment and Intervention and Clinical Science Projects, other candidate neurotoxic agents will similarly be studied for their effects on the adhesion and repulsion critical for normal develop. The long-term objective is to elucidate the mechanisms by which toxic metals an other xenobiotics alter neural pathway formation and synaptic regulation and how consequences of such exposures might be minimized.