MOLECULAR MECHANISMS OF LEAD NEUROTOXICITY

描述：本项目的长期目标是了解 基本的分子机制，铅介导增加 神经递质释放有几条证据支持这一论点 铅会干扰突触负荷的协调调节， 囊泡运动，与突触前膜对接和融合。最近 在体内和体外模型中使用的生化数据提供了 令人信服的证据表明，铅介导的正常干扰 囊泡运输过程导致不适当的释放 神经肌肉中的神经递质在不适当的释放 神经肌肉接头、突触体和 透化细胞培养物。在答复中获得的初步数据 先前的审查进一步加强了首席研究员的断言 铅对突触释放的影响 神经递质可以通过与调节蛋白结合来介导 突触结合蛋白然而，铅诱导的自发放电的确切机制尚不清楚。 神经递质释放仍有待确定。假设导致 与突触结合蛋白结合，因此刺激突触结合蛋白的非预定释放。 神经递质通过三个具体目标来解决。提出 实验旨在了解（1）铅的药理学， 与钙依赖性调节蛋白synaptotagmin结合;（2） 铅-突触结合蛋白复合物在非计划性 神经递质的释放;（3）改变铅的影响， 本修订版提交文件中提出的建议可能会提供新的见解， 铅在正常突触囊泡功能紊乱中的作用。

DESCRIPTION: The long-term goal of this project is to understand fundamental molecular mechanisms by which lead mediates increased neurotransmitter release. Several lines of evidence support the thesis that lead interferes with the coordinated regulation of synaptic loading, vesicular movement, docking and fusion with presynaptic membranes. Recent biochemical data, employing in the vivo and in the vitro models, provides compelling evidence implicating lead-mediated perturbation of normal vesicular trafficking processes resulting in the inappropriate release of neurotransmitters in the neuromuscular in the inappropriate release of neurotransmitters in the neuromuscular junction, synaptosomes and in the permeabilized cell cultures. Preliminary data obtained in the response to previous review further strengthens the principal investigator's assertion that the effects of lead on ephaptic synaptic release of neurotransmitters may be mediated by binding to the regulatory protein synaptotagmin. However, the exact mechanism(s) of lead-induced spontaneous neurotransmitter release remain to be determined. The hypothesis that lead binds to synaptotagmin and, therefore, stimulates unscheduled release of neurotransmitters is addressed by three specific aims. Proposed experiments are aimed at understanding (1) the pharmacology of lead- binding to the calcium-dependent regulatory protein, synaptotagmin; (2) the role of lead-synaptotagmin complexes in the unscheduled neurotransmitter release; and (3) the alteration of lead-effects on proposed in the this revised submission may provide new insights into the role of lead in the perturbation of normal synaptic vesicular function.