MOLECULAR MECHANISM OF SCHWANN CELL MYELINATION

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。在脊椎动物神经系统中，髓磷脂是一种多层膜绝缘体，它包围着轴突并促进快速的神经通讯。我们正在研究在CNS神经胶质中表达P0而不是PLP的基因工程小鼠。令人惊讶的是，在PLP的情况下，P0提供了一个良好的有序结构的小鼠CNS髓鞘，但有序的结构类似于在哺乳动物外周神经系统（PNS）髓鞘中发现的，其中P0是主要的结构蛋白。因此，PLP和PO的存在或不存在似乎定义了髓鞘的有序结构。然而，这些小鼠的寿命减少了50%，可能是因为轴突变性。在CNS髓鞘中具有等量P0和PLP的小鼠具有正常的寿命并且没有轴突变性。这项研究的目的是阐明轴突变性前有髓鞘轴突的变化。初步研究表明，在轴突运输或附近的朗维尔节点的改变。我们怀疑，轴突细胞骨架的三维组织在节点区域改变。这一假设可以用高压显微镜和NCMIR常规使用的厚切片进行检验。 第二个项目涉及观察多发性硬化症（MS）患者的脊髓。慢性脱髓鞘轴突的变性是MS患者不可逆神经功能障碍的主要原因。神经保护疗法的发展需要阐明神经元和轴突退化的分子机制。Perkins博士将帮助我们使用电子断层扫描来表征MS脊髓中存在的线粒体的结构异常。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. IIn the vertebrate nervous system, myelin is a multilayer membrane insulation that surrounds axons and promotes rapid nerve communication. We are investigating genetically engineered mice that express P0 instead of PLP in CNS glia. Surprisingly, in the absence of PLP, P0 provided a well ordered structure to mouse CNS myelin, but the ordered structure resembled that found in mammalian peripheral nervous system (PNS) myelin where P0 is the major structural protein. Thus, the presence or absence of PLP and P0 appears to define the ordered structure of myelin. However, the lifespan of these mice was reduced by 50%, presumably because of the axonal degeneration. Mice with equal amounts of P0 and PLP in CNS myelin had normal lifespans and no axonal degeneration. The purpose of the proposed investigation is to elucidate changes in the myelinated axon that precede axonal degeneration. Preliminary studies indicate alterations in the axonal transport at or near nodes of Ranvier. We suspect that the 3-dimentional organization of axonal cytoskeleton is altered in nodal regions. This hypothesis can be tested with the high voltage microscope and thick sections routinely used at the NCMIR. A second project involves looking at the spinal cord from multiple sclerosis (MS) patients Degeneration of chronically demyelinated axons is a major cause of irreversible neurological disability in MS patients. Development of neuroprotective therapies will require elucidation of the molecular mechanisms by which neurons and axons degenerate. Dr. Perkins will help us to characterize the structural abnormalities of mitochondria present in MS spinal cord using electron tomography.