FAST AXONAL TRANSPORT IN NEURONS

神经元中的快速轴突运输

基本信息

批准号：
3400728
负责人：
ANTHONY C BREUER
金额：
$ 17.31万
依托单位：
CLEVELAND CLINIC FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
1983
资助国家：
美国
起止时间：
1983-12-01 至 1991-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3400728
关键词：
arginine vasopressin axon biopsy calcium metabolism degenerative motor system disease electron microscopy growth cones human subject ion transport laboratory mouse laboratory rat motor neurons neural fasciculation neural information processing neuroanatomy neurogenesis neuronal guidance neuronal transport neurophysiology organelles parathyroid hormones videotape /videodisc

arginine vasopressin axon biopsy calcium metabolism degenerative motor system disease electron microscopy growth cones human subject ion transport laboratory mouse laboratory rat motor neurons neural fasciculation neural information processing neuroanatomy neurogenesis neuronal guidance neuronal transport neurophysiology organelles parathyroid hormones videotape /videodisc

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项目摘要

Information about fast axonal transport in normal and/or diseased mammalian axons (including human) and the regulation of this process is limited. Until this basic information is established, the physiology and pathophysiology of this phenomenon cannot be fully elucidated. We have an opportunity to obtain new basic information on the nature of fast axonal transport in mammalian axons by interfacing sophisticated microscopy, video, and computer technology with ultra-structural analysis and electron probe techniques. We aim to: 1) Pursue our findings of an abnormality in the fast anterograde axonal transport in human amyotrophic lateral sclerosis (ALS) axons by testing the hypothesis that axonal sprouting (as seen in ALS and experimentally reproduced in partially denervated muscle in mice) leads to increased peripheral demand on neuronal somata resulting in augmented organelle delivery rates. Concurrently, we will evaluate the retrograde intra-axonal organelle traffic in the partially denervated mouse model. 2) Test the hypothesis that peptides known to augment intra-axonal organelle traffic speeds may produce neurogenic dysfunction by overloading the neuronal metabolic machinery and/or depleting axonal reserves of critical components when administered chronically. We have shown that both in vitro and in vivo parathyroid hormone treatment will increase fast axonal transport. Hyperparathyroidism in humans can produce an ALS-like syndrome with weakness, muscle atrophy, fasciculation, and neurogenic changes on muscle biopsy. The hypothesis will be tested by sequential subcutaneous implantation (over months) of PTH-loaded Alzet osmotic mimipumps in rats. 3). Test the hypothesis that peptide agonists, specifically PTH, and arginine vasopressin (AVP) increase mean fast organelle traffic speed through the regulation of intracellular calcium. This effort will further probe the thus far unexplored question of regulation of fast axonal transport. 4). Develop further a data base on fundamental aspects of fast organelle transport in mammalian axons in asymmetric segments of neurons and in functionally different classes of neurons. We will evaluate fast axonal transport in a) central vs. peripheral branches of rat dorsal root ganglia, b) sensory vs. motor spinal nerve roots, c) central nervous system vs. peripheral nerve axons and d) myelinated vs. unmyelinated axons. These functionally different axon segment and axon types have not been systematically analyzed for potential differences in fast organelle traffic, differences which might provide clues to the selective vulnerability of different axons in different disease states.

有关正常和/或患病的快速轴突运输的信息哺乳动物轴突（包括人）和对此的调节过程有限。在建立这些基本信息之前这种现象的生理学和病理生理学不能完全阐明。我们有机会获得新的基本有关哺乳动物快速轴突运输的性质的信息轴突通过接口复杂的显微镜，视频和具有超结构分析和电子的计算机技术探针技术。我们的目标是：1）追求我们的发现人类快速顺行轴突运输的异常通过测试假设轴突发芽（如ALS和在小鼠的部分肌肉中进行实验复制）导致对神经元的周围需求增加，导致在增强的细胞器输送率中。同时，我们会的评估逆行轴内细胞器流量部分隐居的鼠标模型。 2）检验以下假设已知可以增加轴内细胞器交通速度的肽通过超负荷神经元可能会产生神经源功能障碍临界的代谢机械和/或耗尽的轴突储备长期给药时组件。我们已经表明体外和体内甲状旁腺激素的治疗都将增加快速的轴突运输。人类的甲状旁腺功能亢进可以产生一个弱点，肌肉的ALS状综合征肌肉活检的萎缩，迷恋和神经源性变化。该假设将通过顺序皮下检验 PTH负载的ALZET渗透的植入（数月以上）模仿大鼠。 3）。检验肽激动剂的假设，特异性PTH和精氨酸加压素（AVP）增加平均值通过细胞内调节的快速细胞器交通速度钙。这项工作将进一步探究迄今未开发的快速轴突运输的调节问题。 4）。发展进一步的数据基础关于快速细胞器的基本方面在神经元的不对称段中的哺乳动物轴突中的运输在功能上不同的神经元中。我们将评估 a）中央与大鼠外围分支的快速轴突运输背根神经节，b）感觉与运动脊神经根，c）中枢神经系统与周围神经轴突和D）髓鞘与无髓的轴突。这些在功能上不同轴突段和轴突类型尚未系统地分析了快速细胞器流量的潜在差异，可能为选择性提供线索的差异不同疾病状态下不同轴突的脆弱性。