ADHESION AND REPULSION MOLECULES IN DEVELOPMENTAL NEUROTOXIC INJURY

发育性神经毒性损伤中的粘附和排斥分子

• 批准号: 6564465
• 负责人: Kenneth Reynolds Reuhl
• 金额: $ 17.91万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2002-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6564465
• 关键词: antioxidants; brain mapping; cadherins; cerebellum; chelating agents; embryo /fetus toxicology; environmental toxicology; gene expression; genetic transcription; genetic translation; gestational age; hippocampus; immunocytochemistry; laboratory mouse; lead poisoning; methylmercury; minerals; neural cell adhesion molecules; neurogenesis; neuropsychological tests; neuropsychology; neurotoxicology; postnatal growth disorder; posttranslational modifications; protein structure function; western blottings

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.

描述（由申请人提供） 神经粘附的适当时间和空间表达 排斥分子，膜蛋白，可提供指导性指导和 支持神经元和神经突运动，对于正常大脑而言至关重要 这些分子的同步表达和功能的干扰已 从微妙的学习障碍到严重的不利后果 畸形。暴露于有毒金属，特别是已知的甲基汞 导致发展和学习不足的行为障碍 成人过程中的过程可能是通过干扰大脑的共同机制 形态发生。假设神经毒性金属扰动大脑 开发/形态发生通过破坏共同调节的表达和 关键的形态调节粘附和排斥分子的功能。到 阐明这些金属的神经毒性作用，四个问题将是 在海马和小脑中检查：1）确实暴露于神经毒性金属 在阶段改变粘附和排斥分子的表达 大脑发育，从而损害形态发生？ 2）选择性 转录，翻译或翻译后过程介导金属诱导的 改变粘附和排斥分子？ 3）行为是什么 毒性干扰的粘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是 通过干预策略进行了修改或改善？ 互补的形态学，生化和行为评估将是 用于表征甲基汞或铅暴露在 粘附分子，NCAM L1，N-钙粘蛋白和EPH拒绝家族 海马中的分子（一生都保持塑料）和小脑 （其中可塑性逐渐消失）。对结构和结构的后果 行为发展将在体内使用，并在体内使用体内和体外来解决 型号。当前的金属毒性临床干预措施将评估 对于分子的影响。随着数据是通过曝光评估而开发的 以及干预和临床科学项目，其他候选神经毒性 同样，将研究代理人对粘附的影响和 排斥对于正常发展至关重要。长期目标是 阐明有毒金属其他异生物元素改变的机制 神经途径形成和突触调节以及这种后果如何 暴露可能会最小化。