MECHANISM OF DEMYELINATION IN MULTIPLE SCLEROSIS

许多原发性脱髓鞘疾病，如在多发性硬化症和 格林-巴利综合征，被广泛认为是由于免疫 过程，其中髓磷脂作为免疫攻击的目标。 的 启动髓鞘分解的机制和受损的髓鞘 在这种情况下被处理的原因是不清楚的。 于过往 研究，对MS和脱髓鞘动物模型的研究倾向于 强调识别和计数免疫活性 细胞、Ab亚型和“脱髓鞘Ab或Ab样因子”的阐明 参与脱髓鞘 现在，是时候研究脱髓鞘的问题了， 从更基础的层面来理解髓磷脂的机制 通过补体（C）、细胞毒性T细胞、NK细胞或K细胞的破坏，和 巨噬细胞，因为这些效应物可能是在炎症中产生的。 脱髓鞘和它们的作用已经被牵连的发病机制 髓鞘破坏 本申请的总体目标是定义生物化学物质， 脱髓鞘事件。 特别强调渠道的作用 在髓鞘/少突胶质细胞的膜上形成。 还将努力 制定了一个统一的概念脱髓鞘，可以拥抱其他 效应细胞如细胞毒性T细胞、NK细胞和K细胞， 靶向膜是C、细胞毒性T细胞和NK细胞之间的共同机制 细胞 巨噬细胞毒因子，被发现是作为细胞毒性， 少突胶质细胞（oligodendrocytes，Lymphocytes，Lymphocytes）结果）也将进行研究。 具体来说，我们将研究是否C通道的形成， 少突胶质细胞和/或髓鞘触发Ca++依赖性髓鞘的活化 中性蛋白酶 Ca++，脂质依赖性蛋白激酶C，产生和 花生四烯酸及其代谢产物和膜脂的释放 甲基转移酶 这些代谢产物的活化 酶如BP和髓鞘相关糖蛋白的蛋白水解， 与髓鞘破坏过程的关系将被研究。

Many primary demyelinating diseases, as observed in Multiple Sclerosis and the Guillain-Barre Syndrome, are widely regarded as due to immunologic processes, in which myelin serves as a target of immune attack. The mechanism(s) by which myelin breakdown is initiated and the damaged myelin is disposed of under these circumstances is poorly understood. In prior research, studies on MS and animal models of demyelination have tended to emphasize the identification and enumeration of immunologically active cells, Ab subtypes and elucidation of "demyelinating Ab or Ab-like factors" participating in demyelination. Now, the time has clearly come to investigate the problems of demyelination at a more fundamental level to understand the mechanisms of myelin destruction by complement (C), cytotoxic T-cells, NK-cells or K-cells, and macrophages because these effectors are likely generated in inflammatory demyelination and their roles have been implicated in the pathogenesis of myelin destruction. The overall objective of this application is to define the biochemical events of demyelination. Particular stress placed on the role of channels formed on the membranes of myelin/oligodendrocytes. Efforts will also be made to develop an unifying concept of demyelination that can embrace other effectors like cytotoxic T-cells, NK-cells and K-cells since channels on target membranes is a shared mechanism among C, cytotoxic T-cells and NK cells. Macrophage cytotoxic factor which was found to be as cytotoxic to oligodendrocytes (Prelim. Results) will also be studied. Specifically, we will examine whether C channel formation on oligodendrocytes and/or myelin triggers activation of Ca++-dependent myelin neutral proteases. Ca++, lipid-dependent protein kinase C, production and release of arachidonic acid and its metabolites and membrane lipid methyltransferases. The metabolic consequence of activation of these enzymes such as proteolysis of BP and myelin associated glycoproteins in relation to the process of myelin destruction will be investigated.