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NEURONAL PERIKARYAL RESPONSES TO NEUROTOXIC CHEMICALS

神经元核周对神经毒性化学物质的反应

基本信息

批准号：
3411979
负责人：
BRUCE G GOLD
金额：
$ 10.01万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-07-01 至 1992-06-30
项目状态：
已结题

项目摘要

The ability to differentiate secondary consequences of toxic chemical exposure from direct toxic effects is an important problem in toxicology. Moreover, in neurons, which can extend long axonal processes, secondary morphological changes may arise in a portion of the cell (e.g. the neuronal perikaryon) far removed from the site of injury. This has led to the search for new probes to decipher these morphological clues. Monoclonal antibodies directed against phosphorylated neurofilament epitopes provide new tools to study pathological alterations and have been applied to several human neurofibrillary disorders, including amyotrophic lateral sclerosis (ALS). In this disorder, phosphorylated epitopes, which are not normally present in neuronal perikarya, are abnormally expressed in cell bodies from affected regions. The significance of these findings remains unknown. It has been suggested that this alteration may be related to a possible defect in neurofilament transport. Alternatively, it may represent a nonspecific response to axonal injury. Animal models employing toxic chemicals offer a means to distinguish between these possibilities. Previous studies following chronic acrylamide administration, which produces axonal degeneration, appear to support the latter possibility. The major hypothesis of the present proposal is that abnormal expression of at least some phosphorylated neurofilament epitopes in neuronal perikarya represents a stereotypic response to axonal injury. This will be tested by correlating the time course of any abnormal expression of phosphorylated epitopes with the development of, 1) proximal swellings in IDPN neuropathy, 2) Distal swellings and axonal degeneration in chronic 2,5-hexanedione (HD) neuropathy, 3) proximal swellings and distal degeneration in 3,4-dimethyl HD (DMHD) neuropathy, and 4) Proximal swellings and degeneration following combined IDPN administration and nerve transection. Furthermore, studies using colchicine will explore the possible role of retrogradely transported "trophic" signals in the initiation of this response. Finally, the relationship between this phenomenon and axonal regeneration will be examined following subepineural acrylamide injection to impair regeneration. These studies may establish a more universal marker for the presence of secondary changes in neuronal perikarya and will clarify the significance of these alterations in several human disorders; e.g. ALS.

区分有毒物质的继发性后果的能力直接毒性作用的化学品暴露是一个重要的毒理学的问题。此外，在神经元中，长轴突过程中，可能会出现继发性形态学变化在细胞的一部分（例如神经元核周体）中，从受伤的地方。这导致了对新探测器的研究来解读这些形态学线索单克隆抗体针对磷酸化的神经丝表位，研究病理变化的新工具，几种人类神经系统疾病，包括肌萎缩性侧索硬化症（ALS）。在这种疾病中，磷酸化表位，通常不存在于神经元胞体中，在受影响区域的细胞体中异常表达。的这些发现的意义仍然未知。已经这一变化可能与一种可能的缺陷有关，在神经丝运输中的作用或者，它可以表示对轴突损伤的非特异性反应。动物模型采用有毒化学物质提供了一种区分这些物质的方法，可能性慢性丙烯酰胺治疗后的既往研究产生轴突变性的给药似乎支持后一种可能性。目前的主要假设是建议是至少一些人不正常表达神经元胞体磷酸化神经丝抗原表位代表了对轴突损伤的刻板反应这将是通过将任何异常表达的时间过程磷酸化表位的发展，1）近端 IDPN神经病变中的脑干，2）远端脑干和轴突慢性2，5-己二酮（HD）神经病变性，3） 3，4-二甲基HD的近端骶管和远端变性（DMHD）神经病变，和4）近端神经病变和变性 IDPN给药和神经切断后。此外，使用秋水仙碱的研究将探索可能的逆行转运的“营养”信号在启动中的作用这一反应。最后，这两者之间的关系以下将检查现象和轴突再生注射丙烯酰胺以损害再生。这些研究可能会建立一个更普遍的标志物，神经元胞体的继发性变化，并将阐明这些改变在几种人类疾病中的意义;例如，人症