Pathogenesis in Segmental Demyelination

项目摘要 摘要：节段性脱髓鞘是髓鞘脱落的病理过程， 电流从轴突流出并导致各种周围神经中动作电位传播失败 疾病然而，导致脱髓鞘的分子程序仍然不清楚，这阻碍了 脱髓鞘性神经病的治疗进展。常染色体隐性基因突变的人 图4基因发展Charcot-Marie-Tooth病4J型（CMT 4J），一种以节段性 脱髓鞘我们在CMT 4J小鼠模型中的初步研究（图4-/-）表明， 脱髓鞘与髓鞘化雪旺细胞和巨噬细胞中细胞内Ca 2+增加有关 在脊神经根中积累。施用Ca 2+螯合剂抑制Fig 4 −/−小鼠的脱髓鞘。 因此，该小鼠成为研究潜在的分子事件的极好模型。 脱髓鞘为此，我们将测试我们的中心假设，即来自FIG 4缺陷轴突的信号 和/或巨噬细胞加剧了FIG 4缺陷型雪旺细胞中细胞内Ca 2+的过载，导致 节段性脱髓鞘我们提出了三个具体的目的：（1）FIG 4缺陷的雪旺细胞对 （2）FIG 4缺陷型巨噬细胞释放细胞因子IL 12 B， FIG 4缺陷的雪旺细胞中细胞内Ca 2+的进一步增加，导致脱髓鞘;（3）个体 PAS复合物中的蛋白质在髓鞘和轴突的发育和维持中具有不同的作用。 这些研究将有可能揭示脱髓鞘的新的分子机制 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.