This research program concerns multiple ongoing projects dealing with the biochemistry, chemistry, and actions of sterols, sphingolipid bases (and their derivatives), and isoprenoid alcohols and acids as well as potential interrelationships in their metabolism and actions. One major project concerns the chemistry, actions, and metabolism of certain 4,4-dimethylsterols very recently found to affect meiosis in mammalian oocytes. Another major focus involves the chemical nature and metabolism of C27 sterols found to accumulate in tissues of subjects with the Smith-Lemli-Opitz syndrome, an hereditary disorder of development associated with a defect in the late stage of cholesterol biosynthesis. Another hereditary disorder of development, suggested to be a defect in squalene epoxidase, is also being studied. Several projects involve studies of the biochemistry and actions of different oxysterols as potential inducers of calcification in specialized cells of arteries (calcifying vascular cells), a subject of importance in the pathogenesis and detection of atherosclerotic lesions. Also included are fundamental studies of the actions of a variety of oxysterols on cholesterol esterification and their actions on acyl coenzyme A-cholesterol acyltransferase, studies of relevance to the intestinal absorption of cholesterol and the pathogenesis of atherosclerosis. Other studies concern the effects of selected oxysterols on the nuclear orphan receptor LXRalpha, recently shown to be important in the in vivo regulation of cholesterol metabolism. Another exciting project concerns studies directed towards determination of the chemical nature of the endogenous inducer(s) of cytochrome P450BM-3 in Bacillus megaterium, with potential for transfer of knowledge from this system to the control of the induction of drug-metabolizing enzymes in humans. Isoprenoid alcohols and acids, regulators of cell growth and apoptosis, will be studied with regard to their syntheses, methods for their separation, and studies of their actions. Sphingolipid bases and their 1-phosphate derivatives, of considerable current interest in biology and medicine, will be studied with regard to their chemistry, methods for their quantitation, and selected actions.
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