Molecular mechanisms of myelin clearance in demyelinating lesions

髓磷脂是由中枢神经系统轴突周围的少突胶质质膜螺旋包裹产生的。其结果是形成紧密堆积的多层膜，由紧密结合和长寿命的分子组成。我们研究了髓磷脂更新的机制以及先天免疫系统在这一过程中的作用。我们现在计划将我们的研究扩展到使用脱髓鞘疾病小鼠模型的疾病。在髓鞘疾病中，大量富含脂质、紧密堆积因而难以消化的髓鞘膜不断被分解并释放到细胞外空间。这种释放不仅会使吞噬小胶质细胞和巨噬细胞的降解能力不堪重负，而且还会导致有毒脂质的积累。在这里，我们想测试小胶质细胞/巨噬细胞中的脂质过载是否代表组织修复中的阿喀琉斯之踵。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中枢神经系统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不适应炎症反应，其中涉及炎性体途径。我们希望我们计划的研究将导致设计新的实验策略，如何促进脱髓鞘病变的脂质外排，以促进脱髓鞘再生和保护神经元免受退化。

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.