MECHANISMS OF COMPLEMENT ATTACK ON NUCLEATED CELLS

许多研究中的红细胞和人工脂质双层 实验室已经获得了膜的基本特征， 补体攻击机制（C）。 因此，我们 在过去的几年里，研究一直致力于 了解C介导的细胞死亡的机制， 代谢活性有核细胞（NC）。 我们发现 NC的细胞溶解需要多个C5 b-9通道，这是由于 防御机制的细胞生存有限的C攻击， 消除潜在的溶解性C通道。 此外该 通道，当以亚裂解数存在时， 增加细胞内Ca 2+并发挥多种生物学效应 例如磷脂酶、脂质甲基转移酶的活化， 细胞中的中性蛋白酶。 我们的课程旨在研究 C5 b-9介导细胞死亡，刺激 细胞修复有限的损伤，并调节细胞功能 与靶细胞的病理生理学相关， 炎症和免疫。 具体来说，我们想确定C诱导的生化 刺激修复过程的信号。 我们亦会研究 其余通道引起的细胞死亡是否完全 取决于胶体渗透调节失调，如果适用， 哪些代谢途径参与了细胞 死亡 此外，我们还将研究代谢性 刺激类似于C5 b-9产生的修复过程 也发生在目标有限的攻击后，通过通道形成 来源于CTL或NK细胞的蛋白质。 我们会继续研究 C8结合蛋白的结构和功能方面， 在同源C5 b-1杀伤和刺激有核细胞中的作用 9. 这些研究，共同，将大大增加我们的 了解补体通道的生物活性 和其它通道形成对NC靶的免疫效应物。

Studies with erythrocytes and artificial lipid bilayers in many laboratories have yielded the fundamental features of membrane attack mechanisms by complement (C). Consequently, our research during the last few years has been devoted to understanding the mechanism(s) of C-mediated cell death in metabolically active nucleated cells (NC). We have found that cytolysis of NC requires multiple C5b-9 channels, due to the defense mechanism of the cell to survive limited C attack by eliminating the potentially lytic C channels. In addition, the channels, when present in sublytic numbers, cause a transient increase in cellular Ca2+ and exert a variety of biological effects such as activation of phospholipases, lipid methyltransferases, and neutral proteases in the cell. Our program is aimed at studying the mechanisms by which C5b-9 mediates cell death, stimulates the cell to repair limited injury, and modulates cellular functions that are relevant to the pathophysiology of the target cells in inflammation and immunity. Specifically, we want to determine the C-induced biochemical signals that stimulate the repair process. We will also investigate whether cell death elicited by the remaining channels is entirely dependent on colloid-osmotic deregulation, and if applicable which metabolic pathways are involved in the process of cell death. In addition, we will examine whether metabolic stimulation of repair processes similar to those produced by C5b-9 also occur in targets following limited attack by channel-forming proteins derived from CTL or NK-cells. We will continue to study the structure and functional aspects of C8-binding protein, and its role in nucleated cell killing and stimulation by homologous C5b- 9. These studies, collectively, will significantly increase our knowledge on the biological activities of complement channels and other channel forming immune effectors on NC targets.