MECHANISMS OF OCCUPATIONAL DISTAL AXONOPATHY

职业性远端轴突病变的机制

• 批准号: 3420255
• 负责人: Peter S Spencer
• 金额: $ 13.19万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-05-01 至 1988-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3420255
• 关键词: acrylamides; axon reaction; central nervous system disorders; gene expression; hereditary peripheral nervous system disorder; messenger RNA; occupational disease /disorder; ornithine decarboxylase; peripheral nervous system disorders

Monomeric acrylamide is an industrially important agent which produces central-peripheral distal axonopathy in humans and laboratory animals following repeated exposure. Acrylamide is one of several chemically unrelated environmental toxins which induce occupational and environmental polyneuropathy and is a useful tool for creating and studying models of axonal degeneration seen in human neuronal degenerative disease of unknown etiology. Preliminary data have demonstrated that single and repeated doses of acrylamide cause dramatic reductions in the rate of retrograde axoplasmic transport, the means by which neuron cell bodies are informed of the need to repair axon damage. In addition, single doses of acrylamide markedly attenuate perikaryal markers of repair-associated gene expression following axotomy of peripheral nerve. This study will investigate the hypothesis that acrylamide-induced axonopathy is the result of a diminished capacity to repair non-specific axon damage resulting from covalent binding of acrylamide. (1) Perikaryl responses to axotomy will be utilized as a model system to study the effects of both single and repeated doses of acrylamide (and equimolar N,N'-methylene-bis-acrylamide) on perikaryal repair processes. This will include measurement of a marker of gene expression (ornithine decarboxylase), RNA synthesis, mRNA synthesis, and synthesis of repair-specific proteins. (2) The effect of single and repeated doses of acrylamide (and equimolar N,N'-methylene-bis-acrylamide) on capacity for regeneration will be studied in detail using biochemical and morphologic techniques. (3) To examine the role of altered repair processes in acrylamide-induced axonopathy, repair processes in peripheral segments of bipolar afferent neurons will be stimulted by central-process transection. If decreased repair capacity is involved in the etiology of acrylamide-induced axonopathy, stimulation of repair will markedly delay or attenuate the pathogenesis of axonopathy. (4) In the converse of experiment (3) above, the hypothesis that altered repair is involved in the etiology of acrylamide-induced axonopathy will be tested by determining if pharmacologic blockade of repair responses renders non-neurotoxic N,N'-methylene-bis-acrylamide neurotoxic. Diminished perikaryal repair capacity, in the presence of low-level axon damage, represents a novel mechanism by which toxic agents may alter neuronal function or structure. Additionally, these studies will provide detailed data regarding the means by which neuronal repair responses are initiated and regulated. It is expected that these studies will substantially further our understanding of how neurotoxic agents alter normal neuronal processes to produce axonopathy.

单体丙烯酰胺是工业上重要的试剂，可产生 人类和实验动物的中枢-外周远端轴突病 反复暴露后。 丙烯酰胺是几种化学物质之一 引起职业和环境的不相关的环境毒素 多发性神经病是创建和研究多发性神经病模型的有用工具 未知的人类神经元退行性疾病中所见的轴突变性 病因学。 初步数据表明，单次和重复 一定剂量的丙烯酰胺会导致逆行率急剧降低 轴浆运输，神经元细胞体获知信息的方式 需要修复轴突损伤。 此外，单剂量丙烯酰胺 显着减弱修复相关基因表达的核周标记 周围神经轴切术后。 本研究将调查 假设丙烯酰胺诱发的轴突病是由于 修复共价结合造成的非特异性轴突损伤的能力 丙烯酰胺。 (1) Perikaryl 对轴切术的反应将被用作 研究单次和重复剂量效果的模型系统 核周丙烯酰胺（和等摩尔 N,N'-亚甲基双丙烯酰胺） 修复过程。 这将包括基因标记的测量 表达（鸟氨酸脱羧酶）、RNA 合成、mRNA 合成和 修复特异性蛋白质的合成。 (2)单项和单项的效果 重复剂量的丙烯酰胺（和等摩尔的 N,N'-亚甲基双丙烯酰胺） 将使用生物化学详细研究再生能力 和形态学技术。 (3) 检验改变修复的作用 丙烯酰胺诱发的轴突病变过程、外周修复过程 双极传入神经元的节段将受到中枢过程的刺激 横断面。 如果修复能力下降是病因之一 丙烯酰胺引起的轴突病变，刺激修复将显着延迟或 减轻轴突病的发病机制。 (4) 反过来 上面的实验（3），假设改变修复涉及 丙烯酰胺诱发的轴突病的病因将通过确定是否 修复反应的药理学阻断使其无神经毒性 N,N'-亚甲基双丙烯酰胺具有神经毒性。 核周修复减弱 在存在低水平轴突损伤的情况下，容量代表了一种新颖的 有毒物质改变神经元功能或结构的机制。 此外，这些研究将提供有关手段的详细数据 通过它启动和调节神经元修复反应。 这是 预计这些研究将大大加深我们对 神经毒剂如何改变正常的神经元过程以产生轴突病变。