The principal goal of this project is to understand the molecular mechanisms utilized by cells for assembling the membrane lipid bilayer. From studies of aqueous equilibrium dispersions of a wide variety of synthetic phospolipids a model for membrane bilayer assembly has been developed which asserts that the membrane bilayer is unilamellar and spontaneously assembles in situ at a critical temperature T*, (the growth temperature), with a composition that is determined by lipids in the metabolic pool of the cell. From studies of the total lipid extracts from erythrocytes, bacteria, and rat cortex, cerebellum and brain stem the model has been shown to be generally applicable to a wide range of cell types and organisms. A corollary of this model for assembly predicts that when temperatures are above or below T* the unilamellar state will transform to multibilayers. For mammalian cells which can synthesize lipid only at body temperatures, it is predicted that when temperatures are raised regions of the membrane will become lipid-deficient because of the unilamellar-multibilayer transformation, and become leaky perhaps leading to cell death. From kinetic studies of erythrocytes and lipid dispersions the transformations have been shown to be very slow processes. It is believed that the slowness of this transformation permits cells to withstand temperature fluctuations around T*. The critical unilamellar state model helps explain why erythrocytes hemolyze under the mild conditions of pyrexia where hemolysis has been observed even with a one degree elevation of body temperature. The instability aspect of this critical bilayer model is currently being tested as a possible basis for membrane failure in Alzheimer's disease.
