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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL041904-08
Application #
6125772
Study Section
Metabolism Study Section (MET)
Project Start
1991-01-01
Project End
2000-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
8
Fiscal Year
2000
Total Cost
$181,547
Indirect Cost
Name
Boston University
Department
Physiology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Guo, Wen; Kurze, Volker; Huber, Thomas et al. (2002) A solid-state NMR study of phospholipid-cholesterol interactions: sphingomyelin-cholesterol binary systems. Biophys J 83:1465-78
Peng, S; Guo, W; Morrisett, J D et al. (2000) Quantification of cholesteryl esters in human and rabbit atherosclerotic plaques by magic-angle spinning (13)C-NMR. Arterioscler Thromb Vasc Biol 20:2682-8
Guo, W; Morrisett, J D; DeBakey, M E et al. (2000) Quantification in situ of crystalline cholesterol and calcium phosphate hydroxyapatite in human atherosclerotic plaques by solid-state magic angle spinning NMR. Arterioscler Thromb Vasc Biol 20:1630-6
Guo, W; Morrisett, J D; Lawrie, G M et al. (1998) Identification of different lipid phases and calcium phosphate deposits in human carotid artery plaques by MAS NMR spectroscopy. Magn Reson Med 39:184-9
Guo, W; Hamilton, J A (1996) 13C MAS NMR studies of crystalline cholesterol and lipid mixtures modeling atherosclerotic plaques. Biophys J 71:2857-68
Bird, D A; Laposata, M; Hamilton, J A (1996) Binding of ethyl oleate to low density lipoprotein, phospholipid vesicles, and albumin: a 13C NMR study. J Lipid Res 37:1449-58
Guo, W; Hamilton, J A (1995) A multinuclear solid-state NMR study of phospholipid-cholesterol interactions. Dipalmitoylphosphatidylcholine-cholesterol binary system. Biochemistry 34:14174-84
Guo, W; Hamilton, J A (1995) Molecular organization and motions of crystalline monoacylglycerols and diacylglycerols: a C-13 MASNMR study. Biophys J 68:1383-95
Guo, W; Hamilton, J A (1995) Phase behavior and crystalline structures of cholesteryl ester mixtures: a C-13 MASNMR study. Biophys J 68:2376-86
Salmon, A; Hamilton, J A (1995) Magic-angle spinning and solution 13C nuclear magnetic resonance studies of medium- and long-chain cholesteryl esters in model bilayers. Biochemistry 34:16065-73

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