MOLECULAR MECHANISMS OF LEAD NEUROTOXICITY

描述：该项目的长期目标是了解 铅调节物质增加的基本分子机制 神经递质释放。有几条证据支持这一论点 这种铅干扰了突触负荷的协调调节， 与突触前膜的囊泡运动、对接和融合。近期 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摄动 泡状贩运过程导致不适当的释放 神经肌肉中神经递质的不适当释放 神经肌肉接头、突触体和脑内的神经递质 渗透性细胞培养。在对以下问题的答复中获得的初步数据 先前的审查进一步加强了首席调查员的断言 铅对触觉突触释放的影响 神经递质可能是通过与调节蛋白结合来调节的 突触集合素。然而，铅致自发性的确切机制(S) 神经递质的释放还有待确定。假设导致了 与突触素结合，从而刺激非计划释放 神经递质有三个具体目标。建议 实验的目的是了解(1)铅的药理作用-- 结合钙依赖调节蛋白--突触素；(2) 铅-突触素复合体在非程序性脑损伤中的作用 神经递质的释放；以及(3)铅对小鼠的影响。 在这份经修订的意见书中提出的建议可能为 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.