NMR STUDIES OF LIPIDS IN DISEASES

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DESCRIPTION: This proposal is a second revision of a renewal application. Briefly, this study will apply state-of-the-art methods of nuclear magnetic resonance (NMR) spectroscopy to characterize the structures of "pathological" lipids in human atherosclerotic plaques (ex vivo) at a molecular level. Magic angle spinning (MAS) solid-state 13C and 31P NMR will be used to identify all major plaque lipids and characterize their physical state (crystalline, liquid crystalline, or liquid) without microdissection and disruption of tissue. Plaques from coronary arteries, carotid arteries, and vein grafts that have failed as a result os lipid accumulation will be studied. The hypothesis that lipid structural organization is related to plaque rupture will be tested. The NMR data derived will also be correlated with magnetic resonance microimages (MRM) of the same sample to give a molecular description (composition and physical states) of lipid-rich regions. It is expected that this calibration of images will lead to new strategies for patient intervention and treatment. 13C and 31P NMR will also be used to study cholesterol interactions and crystallization in model systems for atherosclerosis, including phospholipid bilayers, cell membranes and cells such as macrophage-derived foam cells. These studies are designed to gain a better understanding of how excess cholesterol accumulates in tissues and how this process can be reversed. Finally, the technique of Rotational Resonance Solid-State NMR will be employed to map intramolecular distances in phospholipid bilayers in order to determine the conformation of phospholipid molecules at the bilayer-aqueous interface, and a new two-dimensional 31P NMR method will be explored to discriminate phospholipids with different headgroups for chemical identification and quantitative analysis. Through these techniques, it is hoped that the effects of cholesterol crystallization on the structure of the phospholipid interfacial region can be studied with enhanced resolution.