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不清楚，这阻碍了 脱髓鞘神经病的治疗进展。有常染色体隐性突变的人类 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 髓鞘脱髓鞘与髓鞘雪旺细胞内钙升高和积聚有关 脊神经根中的巨噬细胞。给予钙离子螯合剂抑制图4−/−中的脱髓鞘 老鼠。因此，该小鼠是研究潜在分子事件的合适模型。 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缺陷的雪旺细胞内钙超载，在 转弯，导致节段性脱髓鞘。我们提出了三个具体的目标来验证我们的假设，通过确定 If：(1)FIG4缺乏的雪旺细胞在钙离子刺激下被致敏脱髓鞘；(2)FIG4缺乏 巨噬细胞释放细胞因子IL12B，触发FIG4缺陷的细胞内钙进一步增加 雪旺细胞，导致脱髓鞘；以及(3)PAS复合体中的单个蛋白在 髓鞘和轴突的发育和维持。这些研究有可能发现小说 周围神经病脱髓鞘的分子机制及治疗靶点的确定 发展。

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 demyelination remains unclear, which hampers the therapeutic development for demyelinating neuropathies. Humans with autosomal recessive mutations in the 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 accumulation of macrophages in the spinal roots. Administration of a Ca2+ chelator suppresses the demyelination in Fig4−/− mice. Therefore, this mouse is an appropriate 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 which, in turn, leads to segmental demyelination. We propose three Specific Aims to test our hypothesis by determining if: (1) FIG4-deficient Schwann cells are sensitized to demyelinate upon challenge with Ca2+; (2) FIG4-deficient macrophages release cytokine IL12B that triggers a further increase in intracellular Ca2+ in FIG4-deficient Schwann cells, leading to demyelination; and (3) individual proteins in the PAS complex play distinct roles in the development and maintenance of myelin and axons. These studies have the potential to uncover novel molecular mechanisms underlying demyelinating peripheral neuropathies and identify targets for therapeutic development.