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.
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