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COMPLEMENT--PLASMA MEMBRANE FUNCTIONAL INTERACTIONS

补体--质膜功能相互作用

基本信息

批准号：
6330018
负责人：
ANNE NICHOLSON-WELLER
金额：
$ 34.97万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-07-01 至 2002-11-30
项目状态：
已结题

项目摘要

Complement is a circulating system composed of many different proteins which is known for its ability to lyse animal cells and bacteria. This application seeks support for a series of investigations on the effects of complement on that do not lead to lysis of the target cell: the sublytic events. This proposal stems from our observation that when complement is activated at sublytical concentrations, influx of Na and L-glucose into the unlysed erthrocytes increases dramatically, albeit transiently, and yet the affected cells do not lyse or swell, as would be expected. We found that this non-lethal permeability increase is produced by the membrane attack complex, which is a macromolecular complex of the terminal complement components. Further we determined that C8, but not C9, is necessary to produce the sublytic change in permeability and that in response to the sublytic complement attack, there is activation of a Ca-dependent K permeability pathway. This promotes net K efflux and prevents the colloidosmotic swelling and lysis that occurs when the membrane damage is permanent and permits the survival of the affected cell. In PNH, a disease characterized by a dramatic increase in the sensitivity of erythrocytes to complement lysis, there is apparently a lack of sublytic changes for reasons not yet completely understood. Our specific aims include: 1) continue our studies on the complement regulatory proteins DAF and C8bp, particularly in relation to their role in the sublytic events; 2) characterize further the transient permeability changes and the volume regulatory transport mechanism through studies on ion fluxes during exposure to sublytic complement; and 3) determine the biological consequences of the sublytic events to the cells that survive a complement attack. We will perform studies in normal and PNH erthrocytes, as well as in cells carrying abnormal hemoglobin, such as SS, SC, or CC which are known to have volume regulatory pathways that we predict would decrease their sensitivity to complement lysis. We expect that our investigations will help better understanding complement mediated diseases, such as lupus erythematous and immune hemolytic anemia, and also provide important information on the physiological functions of the complement system and its regulatory proteins.

补体是一个循环系统，由许多不同的蛋白质，以其裂解动物细胞和细菌。此应用程序寻求对一系列补体对非致病因素影响的研究靶细胞的裂解：亚裂解事件。这项建议源于我们的观察，当补体在亚细胞浓度，钠和L-葡萄糖进入细胞内未裂解的红细胞急剧增加，尽管是暂时的，而且然而，受影响的细胞并不像预期的那样溶解或肿胀。我们发现，这种非致命性的渗透率增加是由膜攻击复合体，它是一种大分子复合体终端补充部件。进一步我们确定C8，而不是C9，是产生亚溶质变化所必需的渗透性和对亚溶质补体的反应发作时，钙依赖的钾通透性被激活路径。这会促进净K外流，并防止胶体渗透性肿胀和溶解时发生的膜损伤是永久性的，并允许受影响的细胞存活。在PNH中，一种疾病的特征是红细胞对补体溶解的敏感性，有显然，由于目前还没有的原因，缺乏亚分辨率的改变完全理解。我们的具体目标包括：1)继续我们的补体调节蛋白DAF和C8BP的研究特别是与它们在次要事件中的作用有关；2) 进一步表征了瞬时渗透率的变化和离子通量研究中的体积调节输运机制在接触亚溶血补体的过程中；以及3)确定亚致死事件对细胞的生物学影响在补给攻击中幸存下来。我们将在正常和 PNH红细胞，以及携带异常血红蛋白的细胞，例如已知具有音量调节SS、SC或CC 我们预测的通路会降低它们对补体溶解。我们希望我们的调查能有所帮助。更好地了解补体介导的疾病，如狼疮红斑性和免疫性溶血性贫血，还提供有关细胞生理功能的重要信息补体系统及其调节蛋白。

项目成果

期刊论文数量（28）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Transient changes in erythrocyte membrane permeability are induced by sublytic amounts of the complement membrane attack complex (C5b-9).

DOI：
10.1182/blood.v81.1.200.bloodjournal811200
发表时间：
1993
期刊：
Blood
影响因子：
20.3
作者：
J. Halperin;A. Taratuska;M. Rynkiewicz;A. Nicholson‐Weller
通讯作者：
J. Halperin;A. Taratuska;M. Rynkiewicz;A. Nicholson‐Weller

Paramyosin inhibits complement C1.

DOI：
10.4049/jimmunol.148.1.124
发表时间：
1992-01
期刊：
Journal of immunology
影响因子：
4.4
作者：
J. Laclette;Charles B. Shoemaker;D. Richter;L. Arcos;Nelly Panté;C. Cohen;D. Bing;A. Nicholson‐Weller
通讯作者：
J. Laclette;Charles B. Shoemaker;D. Richter;L. Arcos;Nelly Panté;C. Cohen;D. Bing;A. Nicholson‐Weller

Mechanisms by which the erythrocyte protects itself from complement damage.

红细胞保护自身免受补体损伤的机制。