METHOD TO DETERMINE LATERAL HETEROGENEITY IN BILAYERS

确定双层横向异质性的方法

• 批准号: 2612938
• 负责人: STEVEN L. REGEN
• 金额: $ 17.85万
• 依托单位: LEHIGH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2612938
• 关键词: erythrocyte membrane; hydrogen bond; hydropathy; intermolecular interaction; lipid bilayer membrane; membrane activity; membrane biogenesis; membrane structure; phospholipids

This research program focuses on the development of a new approach to the study of phospholipid organization that is based on the lipid's tendency to form homodimers. This technique has been termed, nearest- neighbor recognition (NNR). Because this method provides unambiguous and quantitative information within fluid bilayers, it represents a unique opportunity for addressing questions that have not previously been possible. The immediate objectives of this research are to synthesize disulfide-based phospholipid dimers that bear exchangeable monomer units that mimic phosphoglycerols, phosphocholines, phosphoethanolamines, and sphingomyelins. These lipids will then be used in NNR experiments to test the following hypotheses: (1) The immiscibility of ester and ether phospholipids will be enhanced when anionic head groups are replaced by ones that are zwitterionic. (2) Differences in head group charge can provide a driving force for lipid segregation. (3) Hydrogen bonding within the head group region, and also the glycerol backbone, can promote lateral heterogeneity. (4) Hydrophobic mismatch between phospholipids and integral peptides can induce lipid clustering. (5) The presence of cationic peptides can promote the lateral separation of anionic from zwitterionic phospholipids. In addition, efforts will be made to extend the NNR method to more complex and more biologically-relevant membranes such as reconstituted erythrocyte ghosts. The long-term objective of this program is to develop a fundamental understanding of the two-dimensional organization of phospholipid membranes in the physiologically-relevant fluid phase. In principle, such an understanding should help to bring exploitable targets (e.g., the plasma membrane of cancer cells, bacterial cells, and fungal cells) into sharper focus, which could assist the rational design of novel classes of therapeutic agents.

该研究计划的重点是开发一种新的方法， 磷脂组织的研究是基于脂质的 形成同源二聚体的趋势。 这项技术被称为，最近的- 邻居识别（NNR）。 因为这种方法提供了明确的 和定量信息，它代表了一种 解决以前没有解决的问题的独特机会 是可能的。 这项研究的直接目标是 合成具有可交换性的基于二硫键的磷脂二聚体 模拟磷酸甘油，磷酸胆碱， 磷酸乙醇胺和鞘磷脂。 然后这些脂质将 在NNR实验中使用，以检验以下假设：（1） 酯和醚磷脂不溶性将增强， 阴离子头基被两性离子头基取代。（二） 头部基团电荷的差异可以为脂质提供驱动力 隔离。(3)头基区域内的氢键，以及 甘油主链可以促进横向异质性。（四） 磷脂和整合肽之间的疏水错配可以 诱导脂质聚集。(5)阳离子肽的存在可以 促进阴离子与两性离子的横向分离 磷脂 此外，还将努力延长NNR 更复杂和更生物相关的膜， 重组红细胞血影 长期目标是 计划是发展二维的基本理解， 磷脂膜的组织在生理相关的 流体相 原则上，这种理解应有助于 可利用的目标（例如，癌细胞的质膜， 细菌细胞和真菌细胞）进入更清晰的焦点， 有助于合理设计新型治疗剂。