REGULATION OF MYELINATION

控制髓鞘基因表达的调控机制 外周神经系统在很大程度上是未知的。进一步认识 转录、翻译和翻译后的调控 髓鞘基因的表达将为推进我们的 对脱髓鞘突出的人类疾病的理解，如 例如，脱髓鞘的周围神经病。迷恋的典范 成年大鼠坐骨神经损伤和永久性横断(经典 沃勒氏退行性变)已被证明是评估 髓鞘基因表达的调控。这些实验动物模型 神经病变的特征是轴突的存在和不存在 再生和随后的髓鞘组装。过去的努力得到了 这笔赠款的重点是周围神经的主要糖蛋白PO 髓鞘，其中转录、翻译和翻译后 已经证实了PO表达的调节。我现在提出一项 概念上的新的研究方向，解决的机制 髓鞘基因的诱导及轴突在此诱导中的作用 正常的、压碎的、永久切断的神经。试点数据为 介绍了Forsklin治疗神经内膜节段的方法 大鼠坐骨神经损伤后cAMP和PO基因表达水平升高 压碎神经，但不是永久切断的神经。这些 结果提供了一个可行的假设，即轴突的存在是 所观察到的cAMP和PO mRNA水平的增加所需，并提示 CAMP的增加发生在轴突内，然后激活一个 不同雪旺细胞第二信使途径诱导PO基因 表情。有人提议用实验来检验这一假说。此外 关于PO监管的进一步描述，我现在计划扩展这一点 其他髓鞘基因及其相关基因的调控分析 产品包括MBP、P2、MAG和CNPase(以及神经节苷脂) 这两个模型作为时间的函数在两种损伤后进行比较 正常成人神经和神经发育过程中的神经。这样的实验将 其他髓鞘相关基因及其产物是否受到监管 以相似或不同的方式。因为这支持了我们的观察 允许PO在翻译后在溶酶体中永久降解 横断性损伤，其他髓鞘损伤的途径和机制 将评估神经横断后蛋白质的分解情况。 了解这些不同的分解代谢途径将有助于破译 不同脱髓鞘人群脱髓鞘机制的观察 神经病。

The regulatory mechanisms that control myelin gene expression in the peripheral nervous system are largely unknown. Further understanding of the transcriptional, translational, and posttranslational regulation of myelin gene expression will provide important information for advancing our understanding of human disease where demyelination is prominent as in, for example, the demyelinating peripheral neuropathies. The paradigms of crush injury and permanent transection of the adult rat sciatic nerve (classical Wallerian degeneration) have proven to be excellent models for evaluating the regulation of myelin gene expression. These experimental animal models of neuropathy are characterized by the presence and absence of axonal regeneration and subsequent myelin assembly. Past efforts supported by this grant have focused on PO, the major glycoprotein of peripheral nerve myelin, where transcriptional, translational, and posttranslational regulation of PO expression has been demonstrated. I now propose a conceptionally new direction of research which addresses the mechanism of myelin gene induction and the role that the axon plays in this induction in the normal, crushed, and permanently transected nerve. Pilot data are presented which demonstrate the forskolin treatment of endoneurial segments of rat sciatic nerve results in increased cAMP and PO mRNA levels in normal and crushed nerves, but not in the permanently transected nerves. These results provide a working hypothesis that the presence of the axon is required for the observed increase of cAMP and PO mRNA levels and suggest that the cAMP increase occurs within the axon which then activates a different Schwann cell second messenger pathway to induce PO gene expression. Experiments are proposed to test this hypothesis. In addition to the further characterization of PO regulation, I now plan to extend this analysis to evaluate the regulation of other myelin genes and their products, including MBP, P2, MAG, and CNPase (as well as gangliosides) in these two models as a function of time after both injuries compared to the normal adult nerve and the nerve during development. Such experiments will address whether other myelin related genes and their products are regulated in similar or different ways. Because of the observation supported by this grant that PO is posttranslationally degraded in lysosomes after permanent transection injury, the pathways and mechanisms by which other myelin proteins are catabolized after nerve transection will be evaluated. Understanding these different catabolic pathways will aid in deciphering the mechanisms of demyelination as observed in various demyelinating human neuropathies.