Molecular mechanisms and functional implications of heterogeneity in myelin structure

少突胶质细胞形态的异质性早在1928年就被Del里约热内卢Hortega描述过。然而，到目前为止，还不能完善少突胶质细胞异质性的概念，并将这些不同的少突胶质细胞亚型与不同的功能联系起来。在这个提议中，我们计划分析亚型少突胶质细胞是否产生具有不同结构和功能特性的髓磷脂。我们认为，在不同口径的轴突髓鞘中，含有细胞质通道的未压缩区域的组织方式存在根本差异。我们的中心假设是，这些细胞质通道为分子运输提供了路径，因此决定了髓磷脂是否能够主动支持轴突。分子组织和潜在的通道的生物发生机制将被解决。此外，还将分析髓鞘损伤和髓鞘再生后细胞质通道的超微结构。总之，我们计划采用一种综合的方法，结合先进的电子显微镜、遗传学和细胞生物学来深入了解复杂膜结构中异质性是如何产生的。如果成功，该项目也可能为我们了解进展性多发性硬化症的发病机制提供新的相关数据。

Heterogeneity of oligodendrocyte morphology was already described by Del Rio Hortega in 1928. However, it has so far not been able to refine the concept of oligodendrocyte heterogeneity and to associate these various oligodendroglial subtypes with different functions. In this proposal we plan to analyze whether subtypes of oligodendrocytes generate myelin with different structural and functional properties. We propose that there are fundamental differences of how the uncompacted areas containing - cytoplasmic channels - are organized in myelin of axons with different calibres. Our central hypothesis is that these cytoplasmic channels provide tracks for molecular transport and therefore determine whether myelin is able to actively support axons. The molecular organization and the mechanism underlying the biogenesis of the channels will be addressed. In addition, the ultrastructure of the cytoplasmic channels will be analyzed after myelin damage and subsequent remyelination. Overall, we plan to use an integrative approach by combining advanced electron microscopy, genetics and cell biology to gain insight into how heterogeneity is generated in a complex membrane architecture. If successful the project may also provide new data relevant for our understanding of the pathogenesis of progressive multiple sclerosis.