The incidence of premature coronary atherosclerosis in the human population. Highly correlated to decreased concentrations of high density lipoprotein or its major apolipoprotein A-I, this condition is referred to as hypoalphalipoproteinemia. The goal of the studies proposed in this application are to elucidate the molecular mechanisms which are responsible for regulating the production of high density lipoproteins at the level of apo-A-I gene expression. In order to clearly define differences based on apo A-I gene expression and to relate these differences to variation in apo A- I production, a recently described model system will be used. It is well established that the African green monkey develops a less severe hypercholesterolemia and atherosclerosis than the cynomolgus monkey when fed levels of cholesterol and fat resembling the North American diet. An important feature of this difference is that African green monkeys have a substantially higher (3 fold) level of plasma HDL and apo A-I concentration than cynomolgus monkeys, factors which may contribute to their greater ability to resist the development of atherosclerosis. Furthermore, apo A-I mRNA abundance in both the liver and small intestine have been found to correlate with the level of hepatic apo A-I production and apo A- I plasma concentration for both the African green and cynomolgus monkey. The studies proposed in this application, therefore, will seek to determine if this species-specific difference in the levels of tissue apo A-I mRNA reflect differences in the regulation and expression of the primate apo A-I gene. To do this, the apo A-I gene will be isolated and sequenced from both African green and cynomolgus monkeys. The degree of sequence homology between the two species will be compared, as well as to the human apo A-I gene sequence. Relative rates of apo A-I transcription will be measured and, the apo A-I mRNA steady state abundance measurements will be correlated to the rates of apo A-I gene transcription for liver and small intestine in both species. 5'flanking sequences of the apo A-I gene for both the African green and cynomolgus monkey will be analyzed by deletion mapping analysis to identify regulatory elements which responsible for species-specific expression of the primate apo A-I gene. The entire apo A-I gene cluster will be investigated in both primate species to determine whether apo A-I, apo C-III and apo A-VI exists as a multi-gene family. The knowledge gained by the completion of these studies will be used to develop strategies for the treatment of hypoalphalipoproteinemia and coronary heart disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HL041916-04
Application #
3472495
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1988-12-01
Project End
1993-11-30
Budget Start
1991-12-01
Budget End
1992-11-30
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Type
Schools of Medicine
DUNS #
041418799
City
Winston-Salem
State
NC
Country
United States
Zip Code
27106
Shanker, G; Sorci-Thomas, M; Adams, M R (1995) Estrogen modulates the inducible expression of platelet-derived growth factor mRNA by monocyte/macrophages. Life Sci 56:499-507
Sorci-Thomas, M; Kearns, M W (1995) Species-specific polymorphism in the promoter of the apolipoprotein A-I gene: restoration of human transcriptional efficiency by substitution at positions -189, -144 and -48 bp. Biochim Biophys Acta 1256:387-95
Shanker, G; Sorci-Thomas, M; Register, T C et al. (1994) The inducible expression of THP-1 cell interleukin-1 mRNA: effects of estrogen on differential response to phorbol ester and lipopolysaccharide. Lymphokine Cytokine Res 13:1-7
Ettinger, W H; Varma, V K; Sorci-Thomas, M et al. (1994) Cytokines decrease apolipoprotein accumulation in medium from Hep G2 cells. Arterioscler Thromb 14:8-13
Shanker, G; Sorci-Thomas, M; Adams, M R (1994) Estrogen modulates the expression of tumor necrosis factor alpha mRNA in phorbol ester-stimulated human monocytic THP-1 cells. Lymphokine Cytokine Res 13:377-82
Sorci-Thomas, M; Kearns, M W; Lee, J P (1993) Apolipoprotein A-I domains involved in lecithin-cholesterol acyltransferase activation. Structure:function relationships. J Biol Chem 268:21403-9
Varma, V K; Smith, T K; Sorci-Thomas, M et al. (1992) Dexamethasone increases apolipoprotein A-I concentrations in medium and apolipoprotein A-I mRNA abundance from Hep G2 cells. Metabolism 41:1075-80
Sorci-Thomas, M; Hendricks, C L; Kearns, M W (1992) HepG2 cell LDL receptor activity and the accumulation of apolipoprotein B and E in response to docosahexaenoic acid and cholesterol. J Lipid Res 33:1147-56
Sorci-Thomas, M; Kearns, M W (1991) Transcriptional regulation of the apolipoprotein A-I gene. Species-specific expression correlates with rates of gene transcription. J Biol Chem 266:18045-50