HDL, both in humans and animal models, has been shown to be atheroprotective. Human HDL is heterogeneous and consists of two major subclasses, HDL2 and HDL3. Epidemiological studies suggest that HDL2 is more atheroprotective than HDL3. Mice and pigs have a monophasic HDL profile. In mice the HDL is close in size and density to human HDL2, and in pigs it is similar to HDL3. The primary goals of this proposal are to generate a mouse model in which HDL2 or HDL3 are the predominant HDL subclass and to test the atheroprotective effects of HDL2 and HDL3 in a well characterized murine atherosclerotic model. In the first specific aim we will use site-directed mutagenesis to make human apoA-I mutants or human/mouse and human/pig chimeric apoA-I and determine if they demonstrate a preferential association in vitro with mature human HDL2 or HDL3, respectively. Our goal is to generate a protein with minimum sequence differences from human apoA-I. Based on our preliminary data we will initially focus on the interhelical turn between helices 7/8. This turn region will be substituted with human interhelical turns containing proline residues or with interhelical turns from mouse or pig.
Our second aim will be to demonstrate that selected apoAI mutants characterized in specific aim 1 can generate HDL2 and HDL3 in vivo in apoA-I deficient mice by adenoviral mediated gene transfer. The, third specific aim will test the efficacy of the engineered HDL2 and HDL3 in protecting against the development of atherosclerosis in human apoB transgenic mice expressing, as knockin genes, the apoA-I proteins that best form HDL2 and HIDL3. The final specific aim will examine how the mutants or the engineered HDLs generated in vivo interact with enzymes and receptors that are involved in HDL remodeling and cholesterol efflux.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068661-04
Application #
6933804
Study Section
Pathology A Study Section (PTHA)
Program Officer
Applebaum-Bowden, Deborah
Project Start
2002-08-01
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
4
Fiscal Year
2005
Total Cost
$381,250
Indirect Cost
Name
University of Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
005421136
City
Chicago
State
IL
Country
United States
Zip Code
60637
Getz, Godfrey S; Reardon, Catherine A (2017) Genetic control of apoprotein A-I and atheroprotection: some insights from inbred strains of mice. Curr Opin Lipidol 28:403-407
Sontag, Timothy J; Carnemolla, Ronald; Vaisar, Tomas et al. (2012) Naturally occurring variant of mouse apolipoprotein A-I alters the lipid and HDL association properties of the protein. J Lipid Res 53:951-63
Wool, Geoffrey D; Cabana, Veneracion G; Lukens, John et al. (2011) 4F Peptide reduces nascent atherosclerosis and induces natural antibody production in apolipoprotein E-null mice. FASEB J 25:290-300
Getz, G S; Wool, G D; Reardon, C A (2010) HDL apolipoprotein-related peptides in the treatment of atherosclerosis and other inflammatory disorders. Curr Pharm Des 16:3173-84
Getz, Godfrey S; Wool, Geoffrey D; Reardon, Catherine A (2010) Biological properties of apolipoprotein a-I mimetic peptides. Curr Atheroscler Rep 12:96-104
Wool, Geoffrey D; Vaisar, Tomas; Reardon, Catherine A et al. (2009) An apoA-I mimetic peptide containing a proline residue has greater in vivo HDL binding and anti-inflammatory ability than the 4F peptide. J Lipid Res 50:1889-900
VanderLaan, Paul A; Reardon, Catherine A; Thisted, Ronald A et al. (2009) VLDL best predicts aortic root atherosclerosis in LDL receptor deficient mice. J Lipid Res 50:376-85
Wool, Geoffrey D; Reardon, Catherine A; Getz, Godfrey S (2008) Apolipoprotein A-I mimetic peptide helix number and helix linker influence potentially anti-atherogenic properties. J Lipid Res 49:1268-83
Carnemolla, Ronald; Ren, Xuefeng; Biswas, Tapan K et al. (2008) The specific amino acid sequence between helices 7 and 8 influences the binding specificity of human apolipoprotein A-I for high density lipoprotein (HDL) subclasses: a potential for HDL preferential generation. J Biol Chem 283:15779-88
Wool, G D; Reardon, C A (2007) The influence of acute phase proteins on murine atherosclerosis. Curr Drug Targets 8:1203-14

Showing the most recent 10 out of 15 publications