Molecular mechanisms of myelin clearance in demyelinating lesions

髓鞘是由少突胶质细胞质膜螺旋缠绕在中枢神经系统轴突周围产生的。其结果是形成紧密堆积的多层膜，由紧密缔合的长寿命分子组成。我们已经研究了髓磷脂周转的机制和先天免疫系统在这一过程中的贡献。我们现在计划将我们的研究扩展到使用脱髓鞘疾病的小鼠模型的疾病。在髓鞘疾病中，大量富含脂质、紧密堆积且因此难以消化的髓鞘膜不断地被分解并释放到细胞外空间中。这样的释放不仅可能压倒吞噬小胶质细胞和巨噬细胞的降解能力，但也可能导致有毒脂质species. There的积累，我们想测试是否脂质过载在小胶质细胞/巨噬细胞代表组织修复的阿喀琉斯之踵。我们的目的是研究小胶质细胞/巨噬细胞中的脂质过载是否会导致CNS脱髓鞘病变的炎症反应、髓鞘再生抑制和神经毒性。我们假设这些事件触发了小胶质细胞的适应不良炎症反应，其中涉及炎症体pathway.我们希望我们计划的研究将导致设计新的实验策略，如何促进脂质从脱髓鞘病变流出，以促进髓鞘再生和保护神经元免于变性。

Myelin is generated by the spiral wrapping of oligodendrocyte plasma membrane around axons of the central nervous system. The result is the formation of tightly packed multilamellar membrane composed of closely associated and long-lived molecules. We have studied the mechanisms of myelin turnover and the contribution of the innate immune system in this process. We now plan to extend our studies to diseases using mouse models of demyelinating disorders. In myelin disorders large amounts of lipid-rich, tightly packed and, thus, hard-to-digest myelin membrane are constantly broken down and released into the extracellular space. Such a release may not only overwhelm the degradation capacities of the phagocytising microglia and macrophages, but could also result in the accumulation of toxic lipid species.Here, we want to test whether lipid overloading in microglia/macrophages represents the Achilles heel in tissue repair. We aim to study whether lipid overload in microglia/macrophages results in an inflammatory response, inhibition of remyelination and neurotoxicity in demyelinated lesions of the CNS. We hypothesize that these events triggers a maladaptive inflammatory response in microglia which involves the inflammasome pathway.We hope that our planed research will lead to the design of novel experimental strategies of how to promote lipid efflux from demyelinating lesions in order to promote remyelination and protect neurons from degeneration.