MECHANISMS OF DYING BACK NEUROPATHIES

神经病消退的机制

基本信息

批准号：
3253314
负责人：
MOHAMED B ABOU DONIA
金额：
$ 11.7万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-02-01 至 1994-01-31
项目状态：
已结题

项目摘要

The goal of this proposal is to examine the mechanism(s) through which covalent binding of neurotoxicants (acrylamide, carbon disulfide (CS2), 2,5-hexanedione (2,5-HD)), to cytoskeletal proteins produces a dying back type of neuropathy. The present study is motivated by the pathological findings that many compounds which covalently bind with specific amino acid residues produce a dying back type of neuropathy. Common neuropathological features of many of these types of neuropathies include axonal swellings which may contain a high number of neurofilaments. Understanding the underlying mechanism which produces this type of neuropathy is primarily important for the elucidation of chemically induced injury to nerve cells. The hypothesis of this proposal is that acrylamide, carbon disulfide, and aliphatic hexacarbons directly interfere with neurofilament function. Several possible alterations of neurofilament biochemistry will be investigated. The mechanisms through which these alterations occur involve a direct binding of the toxicant to neurofilament proteins, an inhibition of protein phosphorylation, an inhibition of proteolytic proteins. The specific aims of this proposal are (1) to examine the in vitro and in vivo covalent binding of [14C]labeled neurotoxicant to cytoskeletal and identification of the amino acid residue which is bound, (2) to study in vitro protein phosphorylation after in vitro incubation with neurotoxicants or in vivo exposure to neurotoxicants, (3) to study in vitro and in vivo proteolytic breakdown of neurofilaments, (4) to examine the reconstitution of neurofilaments after in vitro exposure of neurofilaments to chemicals, (5) to study the interaction of neurofilaments with microtubules and microtubule associated proteins in vitro after in vivo exposure of cytoskeletal proteins, (6) Quantitate change in specific epitopes of neurofilament proteins (i.e. phosphorylated versus de-phosphorylated epitopes) after exposure to these chemicals, and (7) to determine if a protein kinase which is associated with neurofilaments is specifically altered by vivo treatment or in vitro incubation with these neurotoxicants.

该提案的目标是检查以下机制：神经毒物（丙烯酰胺、二硫化碳 (CS2)、 2,5-己二酮 (2,5-HD))，对细胞骨架蛋白产生垂死作用神经病的类型。本研究的动机是病理学研究发现许多与特定氨基酸共价结合的化合物残留物会产生一种垂死的神经病。常见的神经病理学许多此类神经病的特征包括轴突肿胀其中可能含有大量的神经丝。了解产生这种类型的神经病的根本机制主要是对于阐明化学诱导的神经细胞损伤很重要。该提案的假设是丙烯酰胺、二硫化碳和脂肪族六碳化合物直接干扰神经丝功能。神经丝生物化学的几种可能的改变将是调查了。这些改变发生的机制涉及毒物与神经丝蛋白直接结合，产生抑制作用蛋白质磷酸化，抑制蛋白水解蛋白。这该提案的具体目标是（1）检查体外和体内 [14C]标记的神经毒剂与细胞骨架共价结合鉴定结合的氨基酸残基，（2）研究与神经毒物体外孵育后的体外蛋白质磷酸化或体内暴露于神经毒物，（3）进行体外和体内研究神经丝的蛋白水解分解，（4）检查重建神经丝体外暴露于化学物质后的神经丝， (5) 研究神经丝与微管的相互作用体内暴露后体外微管相关蛋白细胞骨架蛋白，(6) 定量特定表位的变化神经丝蛋白（即磷酸化与去磷酸化表位）暴露于这些化学物质后，（7）确定是否与神经丝相关的蛋白激酶特别是通过体内治疗或体外与这些神经毒物一起孵育而改变。