BIOCHEMISTRY OF BACTERIAL CELL MEMBRANES

细菌细胞膜的生物化学

• 批准号: 3124589
• 负责人: HIROSHI NIKAIDO
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1976
• 资助国家: 美国
• 起止时间: 1976-03-01 至 1991-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3124589
• 关键词: Escherichia coli; Salmonella; antibody formation; bacterial genetics; cell differentiation; cell free system; cell fusion; cell membrane; cell wall; electron microscopy; electron spin resonance spectroscopy; gram negative bacteria; immunochemistry; intercellular connection; lipopolysaccharides; membrane activity; membrane permeability; membrane reconstitution /synthesis; membrane structure; molecular biology; monoclonal antibody; nuclear magnetic resonance spectroscopy; phospholipids; ribosomes

The fundamental functions of biological membranes are to serve as general permeation barriers and at the same time allow the selective permeation of certain types of molecules. The structural basis of these functions will be studied at the molecular level by using three different membrane systems. (1) The outer membrane, located outside the cytoplasmic membrane and peptidoglycan layer of Gram-negative bacteria, is an ideal model membrane for the study of this type, because its functions are very simple in that it allows only passive and facilitated diffusion processes. The diffusion of hydrophilic molecules is mediated by porin and other channels, and it is proposed to characterize the properties of these channels in detail. Furthermore, the lipid domains of the outer membrane show an unusually high resistance tothe diffusion of hydrophobic molecules. By studying the molecular basis of this resistance by the use of mutants, agents that increase the permeability of this domain, and various biophysical techniques, we hope to gain insight on the molecular basis of the barrier property of this unusual lipid bilayer. The results of these two lines of work will be of potential medical significance, because the most effective weapon of many gram-negative opportunistic pathogens that are currently causing problems in hospital-related infections is the generalized antibiotic resistance caused by the low permeability of the outer membrane. Thus the outcome of this study will be able to provide methods for increasing the permeability of chemotherapeutic agents through the outer membrane, either via the modification of their structures so that they can pass through the porin channel more rapidly, or by interfering with the organization of the lipid domains so that their permeability to all agents are increased. (2) The molecular mechanism of active transport of maltose will be studied by characterizing the protein components and eventually by attempting reconstitution. "Binding-protein-dependent" transport systems such as this one are not understood at all in terms of their mode of action, and this study is hoped to serve as a model for many such systems that operate in various Gram-negative bacteria. (3) Finally, the properties of the gap junction channel, which connects the cytoplasms of the neighboring animal cells, will be studied by reconstitution approach. This study has implications in the study of cellular differentiation and of the process of development of tumors, as the disappearance of gap junction channel is one of the earliest events in the development of solid tumor.

生物膜的基本功能是起一般作用。 渗透屏障，同时允许选择性渗透 某些类型的分子。这些职能的结构基础将是 用三种不同的膜在分子水平上进行研究 系统。(1)外膜，位于细胞质膜外 而革兰氏阴性菌的多糖层，是一个理想的模型 用于研究这种类型的膜，因为它的功能非常简单 因为它只允许被动和便利的扩散过程。这个 亲水性分子的扩散由孔蛋白和其他通道介导， 并建议用来刻画这些信道的特性 细节。此外，外膜的脂类结构域显示 对疏水分子扩散具有极高的抵抗力。通过 利用突变体研究这种抗性的分子基础， 增加这一领域渗透性的药物，以及各种 生物物理技术，我们希望洞察分子基础 这种不同寻常的脂类双层的阻隔性能。这些研究的结果 有两项工作将具有潜在的医学意义，因为 许多革兰氏阴性条件致病菌最有效的武器 目前在医院相关感染中造成问题的是 沙门氏菌低渗透性引起的广泛性耐药性 外膜。因此，这项研究的结果将能够提供 提高化疗药物渗透性的方法 外膜，或者通过改变它们的结构，从而 它们可以更快地通过孔道，或通过干扰 利用脂域的组织，使其通透性 所有特工都增加了。(2)主动转运的分子机制 麦芽糖的研究将通过表征蛋白质成分和 最终通过尝试重建。“结合蛋白依赖型” 像这样的运输系统根本不被理解为 他们的行动模式，这项研究希望能作为许多人的榜样 这样的系统在各种革兰氏阴性细菌中运行。(3)最后， 连接细胞质的缝隙连接通道的特性 邻近的动物细胞，将通过重组进行研究 接近。这项研究对细胞的研究具有重要意义。 肿瘤分化和发展过程的研究，如 缝隙连接通道的消失是最早的事件之一 实体瘤的发展。