REGULATION OF MYELINATION

髓鞘基因表达的调控机制 周围神经系统在很大程度上是未知的。 进一步理解 转录、翻译和翻译后调节 髓磷脂基因的表达将为推进我们的研究提供重要信息。 了解人类疾病，其中脱髓鞘是突出的，因为 例如脱髓鞘性周围神经病变。 暗恋的典范 损伤和永久性切断成年大鼠坐骨神经（经典 Wallerian变性）已被证明是评估 髓鞘基因表达的调控。 这些实验动物模型 神经病变的特点是存在和缺乏轴突 再生和随后的髓鞘组装。 过去的努力得到了 该基金主要用于外周神经的主要糖蛋白PO 髓磷脂，其中转录、翻译和翻译后 PO表达的调节已被证实。 我现在提出一个 概念上新的研究方向，解决机制， 髓鞘基因的诱导和轴突在这种诱导中的作用， 正常的，被压碎的，永久性切断的神经 导频数据 显示毛喉素治疗神经内膜段 结果表明，大鼠坐骨神经损伤后，正常坐骨神经组织cAMP和PO mRNA水平升高， 和压碎的神经，但不是在永久性切断的神经。 这些 结果提供了一个工作假设，即轴突的存在是 所需的观察到的cAMP和PO mRNA水平的增加，并建议 cAMP的增加发生在轴突内，然后激活了一个 不同的雪旺细胞第二信使途径诱导PO基因 表情 提出实验来检验这一假设。 此外 为了进一步描述PO监管的特征，我现在计划将其扩展到 分析以评估其他髓磷脂基因的调节及其 产品，包括MBP，P2，MAG和CNE（以及神经节苷脂）， 这两个模型作为两种损伤后时间的函数， 正常成人神经和发育中的神经。 这些实验将 解决其他髓鞘相关基因及其产物是否受到调控 以相似或不同的方式。 由于这一观察所支持的 假设PO在溶酶体中被永久降解后， 横断损伤，其他髓鞘 将评估神经横切后蛋白质的分解代谢。 了解这些不同的分解代谢途径将有助于破译 在各种脱髓鞘人类中观察到的脱髓鞘机制 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.