The studies proposed herein will provide new insights into the early steps of atherogenesis. We hypothesize that as macrophages come into contact with matrix-retained LDL aggregates, rapid cholesterol ester transfer occurs. This results in an increase in macrophage membrane cholesterol levels and changes in cell morphology and migratory ability. This process may explain why macrophages within atherosclerotic lesions continue to take up retained lipoproteins and develop into nonmotile foam cells. To investigate this hypothesis, time-lapse confocal fluorescence imaging of in vitro tissue cultures will be utilized to examine macrophage morphological alterations induced during their initial contact with matrix-associated lipoproteins. Further, monitoring the transfer of a fluorescent cholesterol analog from LDL to macrophages allows direct observation of changes in plasma membrane cholesterol levels. Finally, studies will extend our observations on in vitro tissue models to in vivo examination of macrophage migratory behavior in animal models of atherosclerosis. Intravital microscopy will be used for quantification of monocyte/macrophage diapedesis. Results may eventually lead to innovative methods of promoting atherosclerotic lesion regression. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32HL084986-01
Application #
7110424
Study Section
Special Emphasis Panel (ZRG1-F10-H (20))
Program Officer
Meadows, Tawanna
Project Start
2006-04-15
Project End
2009-04-14
Budget Start
2006-04-15
Budget End
2007-04-14
Support Year
1
Fiscal Year
2006
Total Cost
$45,976
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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Takimoto, Eiki; Koitabashi, Norimichi; Hsu, Steven et al. (2009) Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice. J Clin Invest 119:408-20
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