Axonal Protection by Myelin-Associated Glycoprotein (MAG)

描述（由申请人提供）：我们的总体目标是研究脱髓鞘后介导轴突变性的胶质-轴突信号机制。虽然已经确定脱髓鞘可以引起轴突变性，但是这种轴突变性的分子机制仍然不清楚。由于髓鞘形成细胞（MFC的）可以调节轴突的特性，我们推测髓鞘形成改变了下面的轴突的相互作用的配体在近轴质膜的MFC的和受体上的interodal轴膜的轴突。脱髓鞘将与近轴质膜中的关键MFC配体的损失相关，从而损失与轴突受体的关键相互作用。这导致轴突支持的慢性缺陷，导致迟发性轴突变性和对局部炎性介质引起的轴突损失的易感性增加。一个重要的例子是多发性硬化症（MS），其中越来越清楚的是，中枢神经系统（CNS）的脱髓鞘导致进行性和广泛的轴突损失，并导致不可逆的临床缺陷。轴突丢失的类似机制也可能发生在可遗传的人类神经病中，其中髓鞘异常的病症可导致周围神经系统（PNS）中的轴突变性。一种胶质蛋白，髓鞘相关糖蛋白（MAG），已知通过轴突神经丝的磷酸化改变轴突表型。我的初步数据表明，MAG也促进轴突存活在文化和体内。因此，检查MAG-轴突相互作用的拟议研究的具体目的是：1）在培养的神经元中建立MAG保护轴突免受毒性和炎性损伤的测定，2）表征体外轴突存活基础的MAG诱导的信号传导，3）确认和定量缺乏MAG的基因工程小鼠中轴突损失的程度，和4）确认特定分子在MFC/轴突信号传导中的作用，所述MFC/轴突信号传导是遗传工程改造和经LPS处理的小鼠中正常轴突存活的基础。

DESCRIPTION (provided by applicant): Our overall objective is to investigate the glia-axonal signaling mechanism mediating axonal degeneration after demyelination. While it is well established that demyelination can cause axonal degeneration, the molecular mechanism underlying this axonal degeneration remains unclear. Since myelin-forming cells (MFC's) can modulate axonal properties, we speculate that myelination alters the underlying axon by interaction of ligands in the adaxonal plasmalemma of MFC's and receptors on the intenodal axolemma of the axons. Demyelination will be associated with loss of critical MFC ligands in the adaxonal plasmalemma with consequent loss of the critical interaction with the axonal receptor. This results in chronic defect in axonal support, leading to late onset axonal degeneration and increased susceptibility to axonal loss by local inflammatory mediators. One important example is multiple sclerosis (MS), where it is increasingly clear that demyelination of the central nervous system (CNS) results in progressive and extensive axonal loss and contributes to irreversible clinical deficits. A similar mechanism of axonal loss may also occur in the heritable human neuropathies, in which disorders with abnormalities of myelin can lead to axonal degeneration in the peripheral nervous system (PNS). One glial protein, the myelin-associated glycoprotein (MAG), is known to alter axonal phenotype through phosphorylation of axonal neurofilaments. My preliminary data show that MAG also promotes axonal survival in culture and in vivo. Hence, the Specific Aims for the proposed studies to examine MAG-axonal interactions are: 1) to establish assays for axonal protection by MAG from toxic and inflammatory insults in cultured neurons, 2) to characterize the MAG-induced signaling that underlies the axonal survival in vitro, 3) to confirm and quantitate the degree for axonal loss in genetically engineered mice lacking MAG, and 4) to confirm the role of specific molecules in the MFC/axonal signaling that underlies the normal axonal survival in genetically engineered and pharmacologically treated mice.