The overall objective is to apply physical-chemical rationale and techniques to the study of physiological and pathological processes involving lipids. Certain biological fluids (plasma, lymph, bile) contain lipids solubilized or suspended into a pathological distribution of lipids in tissues, cells, and fluids. Such disorders as atherosclerosis or gallstones may result. The plasma membranes of cells and of intracellular organelles contain complex polar lipids which are not soluble but are structured in such a way as to combine fluidity with stability. Membrane composition varies from organelle to organelle and further membranes are asymmetric with respect to both lipid and protein distribution. Membrane composition and asymmetry can be altered by changes in the external environment or by internal metabolic perturbations and such changes may lead to defective function. Inherited deficiencis of enzymes involved in the catabolism of complex phospho- and sphingolipids result in the accumulation of unmetabolized lipids in cellular organelles, membranes and lysosomes. These accumulations affect cell and organ function and give rise to the various familial lipidoses. Finally, certain less polar lipids (occurring for instance in the adipose tissue, adrenal glands, gonads, liver and in the lesions of atherosclerosis) contain lipids in phases separated from the aqueous system. These phases may be liquid or more structured liquid crystalline or crystalline phases. The long term goals are to study the physical state and molecular interactions of lipids and proteins in living systems, to compare them to model systems, to learn how the physical state affects metabolism and vice versa, to understand the molecular basis of normal lipid transport and membrane function and ultimately to understand the molecular basis of conditions in which lipids accumulate, such as atherosclerosis, the lipoproteinemias, and the lipidoses.
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