AXONAL TRANSPORT IN PERIPHERAL NERVE DISEASE

深入研究轴突运输的病理生理学 继续，强调模型和感觉神经病变诱导 对溴苯乙酰脲全身给药大鼠 （BPAU）。 在上一个资助期间取得的成果表明， BPAU神经病变与神经系统的异常有关， 内源性蛋白质的周转和再循环 逆行运输 这些发现意义重大，因为 转弯缺陷可能会导致远端管膜性 BPAU神经病变的轴突病变特征。 此外，委员会认为， 转折异常发生在其他神经症状之前 损害，并与病理的严重程度相称。 目前的研究结果表明，BPAU引起另一个惊人的影响， 运动神经细胞，即在发病的显着缩短 快速运输。 我们将检验缩短的 运输开始反映了一种干扰的处理， 颗粒被组装以输送到轴突中。 三 计划进行多组实验。 首先我们要确定 发作效应是否仅由神经毒素引起 与BPAU相关的酰脲，并发现是否剂量效应 是唯一由与BPAU相关的神经毒性酰脲引起的， 以发现剂量-效应关系是否与 致病作用。 这些实验利用了一系列 BPAU类似物，本地合成的。 第二 一组实验将详细分析BPAU对 颗粒传输和传输转向的动力学。 这 这项工作利用了光学方法的最新进展， 用于粒子运动实时分析的图像处理。 的 第三组实验将探索BPAU 治疗导致可检测的生化变化， 快速运输细胞器的免疫化学性质。 这 这项工作涉及一组单克隆抗体的应用， 在这个实验室产生的表面抗原的内- 轴突细胞器。 总的来说，我们希望增加 对了解毒物的发病机理有重要意义， 诱发性的神经病变

Intensive investigation of the pathophysiology of axonal transport continues, emphasizing the model and sensory neuropathy induced in rats by systemic treatment with p-bromophenylacetylurea (BPAU). Results obtained during the previous funding period show that BPAU neuropathy is associated with abnormalities in the turnaround and recirculation of endogenous proteins by rapid retrograde transport. These findings are significant because turnaround-defects could cause the distal tubulomembranous axonal lesions that characterize BPAU neuropathy. Furthermore, the turnaround-abnormality occurs before other signs of nerve damage and is commensurate with the severity of the pathology. Current results show that BPAU causes another striking effect in motor nerve cells, namely a marked shortening in the onset of rapid transport. We will test the hypothesis that the shortened transport-onset reflects a disturbance in the processing of particles being assembled for delivery into the axon. Three groups of experiments are planned. First we intend to determine whether the onset-effect is uniquely caused by the neurotoxic ureides related to BPAU and to discover whether the dose-effect is uniquely caused by the neurotoxic ureides related to BPAU and to discover whether the dose-effect relations are compatible with a pathogenic role. These experiments make use of a series of BPAU analogues, locally synthesized for the purpose. The second set of experiments will analyze in detail the effect of BPAU on the kinetics of particle transport and transport-turnaround. This work takes advantages of recent advances in optical methods and image-processing for real-time analysis of particle motion. The third set of experiments will explore the possibility that BPAU treatment leads to detectable changes in the biochemical and immunochemical properties of fast transported organelles. This work involves the application of a set of monoclonal antibodies generated in this laboratory to the surface antigens of intra- axonal organelles from rat nerve. Overall we expect to add significantly to understanding of the pathogenesis of toxicant- induced, dying-back neuropathies.