As a result of studies with erythrocytes and artificial lipid bilayers in many laboratories, the fundamental features of membrane attack by complement are now well understood. Consequently, our research during the past year has shifted to studies of the mechanism(s) of complement attack on metabolically active nucleated cells. This shift is motivated by the fact that such cells are directly involved in the physiological and pathological activities of complement, and the recognition that there are large gaps in our knowledge of complement attack on nucleated cells with respect to its mechanism(s) and consequences. Accordingly, our program is aimed at studying the characteristics of complement channels in the membranes of nucleated cells, especially their stability and the modulating effect of certain drugs and hormones, in relation to the cell's capacity for membrane synthesis. Other important issues we plan to study concern the role of metabolic factors in complement-mediated cell death, and the modulation of membrane enzymes during complement interaction with cell membranes. These include the role of calcium flux through the channels in cell death and the mechanism complement-mediated and phospholipase activation and its consequences. Specifically, we want to determine: (1) Whether complement-mediated cell death exhibits single-hit or multi-hit characteristics, (2) whether complement channels in the nucleated cell membrane are stable, (3) how agents that alter membrane lipid synthesis affect the susceptibility to complement-mediated cytotoxicity, (4) how complement activates membrane-associated phospholipase, and (5) which constituent of the cell membrane is responsible for the species restriction with respect to the lytic function of C9. Collectively, we expect that studies will significantly increase our knowledge of the cytotoxic and inflammatory activities of complement in immunity and allergy.
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