? The major goal of this proposal is to determine how triglyceride-rich lipoproteins (TGRL) and their associated apoprotein E (apoE) isoforms interact with endothelial cell plasma membrane micro domains, including lipid rafts, in the postprandial state. Our proposal spans the spectrum from detection of single molecules affecting lipoprotein-endothelial cell interactions to individual human feeding studies. Work from our lab and others have led us to propose the following specific aims: ? ? Aim 1: To determine the conformational properties of apoE3 and apoE4 present on very-low density lipoproteins (VLDL) in the pre- and postprandial states. ? ? Aim 2: To examine apoE3 and apoE4 interactions with endothelial cells in the pre- and postprandial states. ? ? Aim 3: To determine how the pre- and postprandial states modify plasma membrane microstructure. ? ? We have assembled a unique group with expertise covering structural biology, laser spectroscopy and microscopy, lipid biochemistry, vascular biology and clinical nutrition. The combined expertise of this group will enable us to extend our understanding of how lipoproteins interact with endothelium using advanced imaging techniques at the cellular and molecular level. We expect that the molecular level understanding obtained through the proposed work will mark an important step forward in our basic and clinical understanding of how atherosclerotic cardiovascular disease, the greatest single cause of morbidity and mortality in the U.S., is initiated. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL078615-04
Application #
7274831
Study Section
Special Emphasis Panel (ZHL1-CSR-K (S1))
Program Officer
Buxton, Denis B
Project Start
2004-09-22
Project End
2008-08-31
Budget Start
2007-09-01
Budget End
2008-08-31
Support Year
4
Fiscal Year
2007
Total Cost
$546,881
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Lagerstedt, Jens O; Budamagunta, Madhu S; Liu, Grace S et al. (2012) The ""beta-clasp"" model of apolipoprotein A-I--a lipid-free solution structure determined by electron paramagnetic resonance spectroscopy. Biochim Biophys Acta 1821:448-55
Schie, Iwan W; Wu, Jian; Weeks, Tyler et al. (2011) Label-free imaging and analysis of the effects of lipolysis products on primary hepatocytes. J Biophotonics 4:425-34
Lagerstedt, Jens O; Cavigiolio, Giorgio; Budamagunta, Madhu S et al. (2011) Structure of apolipoprotein A-I N terminus on nascent high density lipoproteins. J Biol Chem 286:2966-75
Sriram, Renuka; Lagerstedt, Jens O; Petrlova, Jitka et al. (2011) Imaging apolipoprotein AI in vivo. NMR Biomed 24:916-24
Wang, Limin; Gill, Rajan; Pedersen, Theresa L et al. (2009) Triglyceride-rich lipoprotein lipolysis releases neutral and oxidized FFAs that induce endothelial cell inflammation. J Lipid Res 50:204-13
Wang, Limin; Sapuri-Butti, Annapoorna R; Aung, Hnin Hnin et al. (2008) Triglyceride-rich lipoprotein lipolysis increases aggregation of endothelial cell membrane microdomains and produces reactive oxygen species. Am J Physiol Heart Circ Physiol 295:H237-44
Schie, Iwan W; Weeks, Tyler; McNerney, Gregory P et al. (2008) Simultaneous forward and epi-CARS microscopy with a single detector by time-correlated single photon counting. Opt Express 16:2168-75
Lagerstedt, Jens O; Cavigiolio, Giorgio; Roberts, Linda M et al. (2007) Mapping the structural transition in an amyloidogenic apolipoprotein A-I. Biochemistry 46:9693-9
Lagerstedt, Jens O; Budamagunta, Madhu S; Oda, Michael N et al. (2007) Electron paramagnetic resonance spectroscopy of site-directed spin labels reveals the structural heterogeneity in the N-terminal domain of apoA-I in solution. J Biol Chem 282:9143-9
Kota, Rama S; Rutledge, John C; Gohil, Kishorchandra et al. (2006) Regulation of gene expression in RAW 264.7 macrophage cell line by interferon-gamma. Biochem Biophys Res Commun 342:1137-46

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