This application represents a continuation of a Program Project whose overall goal is to elucidate the contributions of the cholesterol transport functions of high density lipoprotein (HDL) to the prevention of the development of atherosclerosis. The mechanisms by which HDL mediates reverse cholesterol transport (RCT), the process whereby cholesterol is removed from peripheral cells and transported to the liver for clearance from the body, will be investigated. Experiments will be conducted in a coordinated fashion at the molecular, cellular, whole animal and human levels. This Program Project consists of three closely related and interactive projects. Project 1 proposes to investigate using novel assays the effects of HDL quantity and quality on the net flux of cholesterol by different pathways between cells and serum, and the impact on cholesterol flux of the hydrolysis of cholesteryl est droplets in macrophage foam cells. Project 2 aims to understand human apolipoprotein (apo) A-l structure-function and the molecular mechanisms by which this protein binds lipids and creates HDL particles by interaction with the ATP-binding cassette transporter Al. Project 3 involves the use of in vivo methods to understand the molecular regulation of RCT. The mechanisms responsible for the effects of apoA-l mutations and plasma factors (lecithin-cholesterol acyltransferase, cholesteryl ester transfer protein, phospholipid transfer protein) on HDL metabolism and macrophage RCT will be evaluated in mice. New methods for the assessment of RCT in human will be used to examine the influence of HDL quantity and quality in this setting. The group of investigators comprising this Program Project share similar interests and goals in lipid and lipoprotein metabolism while providing broad scientific expertise. The scientific disciplines encompassed by these investigators include biochemistry, cell biology, molecular biology, protein chemistry, animal physiology and medicine. The program is supported by three core laboratories: 1) Administrative/Central Service Core, 2) Tissue Culture Core and 3) Lipoprotein Core. The incidence of premature coronary artery disease is reduced in human populations with elevated levels of plasma HDL cholesterol. The reasons for this protective effect are not understood fully and this project seeks to uncover the molecular mechanisms underlying the beneficial properties of HDL.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
3P01HL022633-35S1
Application #
8434588
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Liu, Lijuan
Project Start
1997-07-01
Project End
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
35
Fiscal Year
2012
Total Cost
$66,400
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Phillips, Michael C (2014) Molecular mechanisms of cellular cholesterol efflux. J Biol Chem 289:24020-9
Yang, Yanbo; Kuwano, Takashi; Lagor, William R et al. (2014) Lipidomic analyses of female mice lacking hepatic lipase and endothelial lipase indicate selective modulation of plasma lipid species. Lipids 49:505-15
Lagor, William R; Fields, David W; Bauer, Robert C et al. (2014) Genetic manipulation of the ApoF/Stat2 locus supports an important role for type I interferon signaling in atherosclerosis. Atherosclerosis 233:234-41
Weibel, Ginny L; Drazul-Schrader, Denise; Shivers, Debra K et al. (2014) Importance of evaluating cell cholesterol influx with efflux in determining the impact of human serum on cholesterol metabolism and atherosclerosis. Arterioscler Thromb Vasc Biol 34:17-25
Nagao, Kohjiro; Hata, Mami; Tanaka, Kento et al. (2014) The roles of C-terminal helices of human apolipoprotein A-I in formation of high-density lipoprotein particles. Biochim Biophys Acta 1841:80-7
Nguyen, David; Nickel, Margaret; Mizuguchi, Chiharu et al. (2013) Interactions of apolipoprotein A-I with high-density lipoprotein particles. Biochemistry 52:1963-72
Chetty, Palaniappan Sevugan; Nguyen, David; Nickel, Margaret et al. (2013) Comparison of apoA-I helical structure and stability in discoidal and spherical HDL particles by HX and mass spectrometry. J Lipid Res 54:1589-97
Patel, Parin J; Khera, Amit V; Wilensky, Robert L et al. (2013) Anti-oxidative and cholesterol efflux capacities of high-density lipoprotein are reduced in ischaemic cardiomyopathy. Eur J Heart Fail 15:1215-9
Alexander, Eric T; Phillips, Michael C (2013) Influence of apolipoprotein A-I and apolipoprotein A-II availability on nascent HDL heterogeneity. J Lipid Res 54:3464-70
Phillips, Michael C (2013) New insights into the determination of HDL structure by apolipoproteins: Thematic review series: high density lipoprotein structure, function, and metabolism. J Lipid Res 54:2034-48

Showing the most recent 10 out of 335 publications