Through the application of physical-chemical rationale and biochemical, biophysical techniques we will continue to define the phase behavior of alimentary tract lipids and lipid-protein systems in health and disease: Phase relations, fine structures and properties of phases encountered in model systems will be correllated with actual pathophysiological phenomena. Those experiments will demonstrate how the delicate physical-chemical balance of lipids and proteins in multicomponent native systems, e.g. bile, gut luminal contents, high density lipoproteins (HDL) are perturbed in disease states and may suggest strategies for their correction. The physical state of native bile will be studied with specific reference to micellar and non-micellar particles, as will their fate when diluted and mixed with pancreatic enzymes and dietary fat emulsions. Cholesterol nucleation and crystallization from bile will be investigated with particular reference to bile proteins, divalent ions and fusogenic bile salts. The origin of lipoprotein X will be defined employing the isolated perfused liver, and its relevance to intracellular bile formation investigated. Phase equilibria and micellar properties of muricholates and ursocholates, hydrophilic bile salts that are potential agents for gallstone dissolution and prevention, will be determined, as will the solution properties of calcium bile salts. Reverse bile salt/fusidate micelles and liquid crystalline phases will be systematically examined as potential vehicles for drug absorption. The influence of cholesterol on phase equilibria and structures of HDL recombinants, as well as HDL-bile salt binding and hepatic HDL-bile salt uptake, will be studied. Synthetic discoid and vesicle HDL with cloned fragments of apo-AI and AII and their secretion into bile will be investigated as possible therapeutic approaches to enhance reverse cholesterol transport and gallstone prevention, respectively. Physical-chemical properties of natural bilirubin conjugates in aqueous systems, in membrane systems, and in bile will be elucidated, and the physical-chemical abnormalities in pigment lithogenic biles will be identified. Finally, using a combination of physical-chemical and pathophysiological methods, we will determine the relative efficacy of intestinal fat absorption from micellar vs. liquid crystalline phases, explore mechanisms of lipid penetration into absorptive cells, and investigate intestinal absorption of therapeutic peptides (insulin, proinsulin, glucagon) from reverse micellar systems and liquid crystalline phases.
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