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，这阻碍了脱髓鞘的发生。 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， 脱髓鞘与髓鞘形成的雪旺细胞中细胞内Ca 2+的增加和积累有关。 脊髓根部的巨噬细胞图4 −/−中给予钙离子螯合剂可抑制脱髓鞘 小鼠因此，该小鼠是研究潜在的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， 转，导致节段性脱髓鞘。我们提出了三个具体目标，以测试我们的假设，确定 如果：（1）FIG 4缺陷的雪旺细胞在用Ca 2+攻击时对脱髓鞘敏感;（2）FIG 4缺陷的雪旺细胞在用Ca 2+攻击时对脱髓鞘敏感。 巨噬细胞释放细胞因子IL 12 B，其触发FIG 4缺陷的细胞内Ca 2+的进一步增加。 雪旺氏细胞，导致脱髓鞘;（3）PAS复合物中的单个蛋白质在 髓鞘和轴突的发育和维持。这些研究有可能揭示新的 脱髓鞘周围神经病变的分子机制，并确定治疗靶点 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.