BIOCHEMISTRY OF BACTERIAL CELL MEMBRANES

细菌细胞膜的生物化学

• 批准号: 3124594
• 负责人: HIROSHI NIKAIDO
• 金额: $ 25.49万
• 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/3124594
• 关键词: Escherichia coli; Salmonella; antibody formation; bacterial genetics; binding proteins; cell differentiation; cell free system; cell fusion; cell membrane; cell wall; electron microscopy; electron spin resonance spectroscopy; gap junctions; gram negative bacteria; immunochemistry; intercellular connection; laboratory mouse; laboratory rabbit; lipopolysaccharides; membrane activity; membrane channels; membrane permeability; membrane proteins; membrane reconstitution /synthesis; membrane structure; molecular biology; monoclonal antibody; nuclear magnetic resonance spectroscopy; phospholipids; protein structure; 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作为一般的 渗透屏障，同时允许选择性渗透 某些类型的分子。 这些功能的结构基础将 通过使用三种不同的膜， 系统. (1)外膜，位于细胞质膜外 和肽聚糖层的革兰氏阴性菌，是一种理想的模型 膜为研究这一类型，因为它的功能非常简单 因为它只允许被动和易化扩散过程。 的 亲水性分子的扩散由孔蛋白和其它通道介导， 并提出了表征这些通道的特性， 详细 此外，外膜的脂质结构域显示出 对疏水分子的扩散具有异常高的抵抗力。 通过 利用突变体研究这种抗性的分子基础， 增加该结构域的渗透性的试剂，以及各种 生物物理技术，我们希望获得深入了解的分子基础上， 这种不寻常的脂质双层的屏障特性。 的结果予以 这两种工作将具有潜在的医学意义，因为 是许多革兰氏阴性机会致病菌的最有效武器， 目前造成医院感染问题的原因是 由细菌的低渗透性引起的广泛的抗生素耐药性 外膜 因此，这项研究的结果将能够提供 用于增加化疗剂渗透性的方法， 外膜，或者通过改变它们的结构， 它们可以更快地通过孔蛋白通道，或者通过干扰 与脂质结构域的组织，使它们的渗透性， 所有代理商都增加了。 (2)主动转运的分子机制 麦芽糖将通过表征蛋白质组分进行研究， 最终通过尝试重组。 “依赖结合蛋白” 像这样的交通系统， 他们的行动模式，这项研究希望作为一个模型，许多 这些系统在各种革兰氏阴性细菌中运行。 (3)最后， 连接细胞壁的差距连接通道的性质 邻近动物细胞的，将通过重组进行研究 approach. 这项研究对细胞的研究有一定的意义。 分化和肿瘤的发展过程中，作为 缝隙连接通道的消失是细胞凋亡中最早的事件之一， 实体瘤的发展。