The broad objective of this program is to identify and understand the principal factors that are responsible for the formation of lipid domains, in the physiologically relevant fluid phase. The possibility that such domains play an important role in (i) the presentation of receptors at the cell surface, and (ii) the activities of membrane-bound enzymes, may have important implications for the rational design of chemotherapeutic agents.
The specific aims of the research which is outlined in this proposal are (1) to develop the thiol-disulfide interchange reaction into a mechanistic tool for studying lipid domains in fluid membranes, and (2) to define the importance of alkyl chain length, head group composition, the presence of cholesterol, and internal membrane pressure on domain formation. The immediate synthetic objective of this program are to prepare a homologous series of symmetrical and asymmetrical disulfide-bridged phosphatidylcholine and phosphatidylethanolamine dimers. Mechanistic studies that are proposed involve the equilibration of selected pairs of phospholipid dimers, via a thiol-disulfide interchange reaction, and an analysis of thermodynamically-controlled product mixtures via high pressure liquid chromagtography and by quantitative thin layer chromatography.
