Abstract

Previous studies from our laboratory have demonstrated that susceptibility to atherosclerosis differs significantly between inbred strains of mice, suggesting a strong genetic component to the disease. Athl is a quantitative trait locus that we found to be associated with decreased plasma HDL-cholesterol levels and increased atherosclerotic lesion formation in susceptible strains of mice when fed a high fat diet. We have recently identified a Athl candidate gene, Aop2, which is a member of the thiol-specific antioxidant family. We believe Aop2 mediates protection from atherosclerosis based on its chromosomal co-localization with Athl, mRNA induction by high fat diet, amino acid and expression differences between resistant and susceptible strains, and the proposed role of LDL oxidation in the pathogenesis of atherosclerosis. I propose three specific aims toward the characterization of AOP2 in atherosclerosis resistance: 1) obtain definitive proof that AOP2 confers resistance to atherosclerosis by transgenic rescue; 2) characterize expression of AOP2 in the arterial wall; and 3) determine the molecular basis for the regulatory differences observed between atherosclerosis resistant and susceptible strains.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
7F32HL010124-02
Application #
6139127
Study Section
Biological Sciences 2 (BIOL)
Project Start
1999-12-12
Project End
Budget Start
1999-12-12
Budget End
2000-12-11
Support Year
2
Fiscal Year
2000
Total Cost
$36,700
Indirect Cost

  Institution

Name
Fairfield University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
City
Fairfield
State
CT
Country
United States
Zip Code
06824

  Publications

Phelan, S A; Wang, X; Wallbrandt, P et al. (2003) Overexpression of Prdx6 reduces H2O2 but does not prevent diet-induced atherosclerosis in the aortic root. Free Radic Biol Med 35:1110-20
Phelan, Shelley A; Beier, David R; Higgins, David C et al. (2002) Confirmation and high resolution mapping of an atherosclerosis susceptibility gene in mice on Chromosome 1. Mamm Genome 13:548-53
Phelan, S A (1999) AOP2 (antioxidant protein 2): structure and function of a unique thiol-specific antioxidant. Antioxid Redox Signal 1:571-84
Glasser, S W; Korfhagen, T R; Weaver, T E et al. (1988) cDNA, deduced polypeptide structure and chromosomal assignment of human pulmonary surfactant proteolipid, SPL(pVal). J Biol Chem 263:9-12
O'Reilly, M A; Nogee, L; Whitsett, J A (1988) Requirement of the collagenous domain for carbohydrate processing and secretion of a surfactant protein, SP-A. Biochim Biophys Acta 969:176-84
McMahan, M J; Mimouni, F; Miodovnik, M et al. (1987) Surfactant associated protein (SAP-35) in amniotic fluid from diabetic and nondiabetic pregnancies. Obstet Gynecol 70:94-8
Whitsett, J A; Pilot, T; Clark, J C et al. (1987) Induction of surfactant protein in fetal lung. Effects of cAMP and dexamethasone on SAP-35 RNA and synthesis. J Biol Chem 262:5256-61
Notter, R H; Shapiro, D L; Ohning, B et al. (1987) Biophysical activity of synthetic phospholipids combined with purified lung surfactant 6000 dalton apoprotein. Chem Phys Lipids 44:1-17
Ross, G F; Ohning, B L; Tannenbaum, D et al. (1987) Structural relationships of the major glycoproteins from human alveolar proteinosis surfactant. Biochim Biophys Acta 911:294-305
Glasser, S W; Korfhagen, T R; Weaver, T et al. (1987) cDNA and deduced amino acid sequence of human pulmonary surfactant-associated proteolipid SPL(Phe). Proc Natl Acad Sci U S A 84:4007-11

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