Pathogenesis in Segmental Demyelination

项目摘要 摘要：节段性脱髓鞘是一种脱髓鞘、分流髓鞘的病理过程。 电流流出轴突，导致动作电位在各种周围神经中传播失败 疾病。然而，导致脱髓鞘的分子程序仍然不清楚，这阻碍了 脱髓鞘神经病的治疗进展。人类常染色体隐性突变 FIG4基因导致4J型Charcot-Marie-Tooth病(CMT4J)，这种疾病的特点是节段性 脱髓鞘。我们在CMT4J小鼠模型(图4−/−)上的初步研究表明，节段性 髓鞘雪旺细胞和巨噬细胞脱髓鞘与细胞内钙离子升高有关 在脊神经根中堆积。给予钙离子螯合剂抑制图4−/−小鼠的脱髓鞘。 因此，这种小鼠成为研究潜在分子事件的极佳模型。 脱髓鞘。为此，我们将测试我们的中心假设，即来自图4缺陷轴突的信号 和/或巨噬细胞加剧FIG4缺陷雪旺细胞内钙超载，导致 节段性脱髓鞘。我们提出了三个特定的目标：(1)FIG4缺陷的雪旺细胞对 钙离子刺激时脱髓鞘；(2)FIG4缺乏的巨噬细胞释放细胞因子IL12B，触发 FIG4缺陷性雪旺细胞内钙进一步升高，导致脱髓鞘；(3)个体 PAS复合体中的蛋白质在髓鞘和轴突的发育和维持中起着不同的作用。 这些研究将有可能揭示脱髓鞘的新分子机制。 此外，我们还将继续研究周围神经病变，并确定治疗发展的目标。

Project Summary Abstract: Segmental demyelination is a pathologic process of stripping off the myelin sheath, which shunts current out of axons and results in the failure of action potential propagation in a variety of peripheral nerve diseases. However, the molecular program that leads to the demyelination remains unclear, which hampers the therapeutic development for demyelinating neuropathies. Humans with autosomal recessive mutations in FIG4 gene develop Charcot-Marie-Tooth disease type-4J (CMT4J), a disease characterized by segmental demyelination. Our preliminary studies in a CMT4J mouse model (Fig4−/−) have demonstrated that segmental demyelination is associated with increased intracellular Ca2+ in myelinating Schwann cells and macrophages accumulation in the spinal roots. Administering a Ca2+ chelator suppresses the demyelination in Fig4−/− mice. Therefore, this mouse becomes an excellent model to investigate the molecular events underlying demyelination. Toward this end, we will test our central hypothesis that signals from FIG4-deficient axons and/or macrophages exacerbate the overload of intracellular Ca2+ in FIG4-deficient Schwann cells, leading to segmental demyelination. We propose three Specific Aims: (1) FIG4-deficient Schwann cells are sensitized to demyelinate upon challenge with Ca2+; (2) FIG4-deficient macrophages release cytokine IL12B that triggers further increases in intracellular Ca2+ in FIG4-deficient Schwann cells, leading to demyelination; (3) Individual proteins in the PAS complex have different roles in the development and maintenance of myelin and axons. These studies will have the potential to uncover novel molecular mechanisms underlying demyelinating peripheral neuropathies and identify targets for therapeutic development.