The objectives of the proposed research are to establish a correlation between variations in apolipoproteins and various human diseases which lead to premature atherosclerosis. These objectives will be realized by further study of a) the structure and function of normal and variant apolipoprotein genes, and b) the biochemical events which control the synthesis and secretion of human apolipoproteins.
The specific aims of the proposed research are: 1) To determine the structure and regulation of expression of human apolipoprotein B; 2) To study the structure and regulation of expression of the apoE gene obtained from patients with plasma apoE deficiency and compare it with the normal apoE gene; 3) To determine cis-acting elements or transacting factors which control the expression of apolipoprotein genes; 4) To study the post translational modifications of apolipoproteins and their importance for lipoprotein metabolism. The structure of human apolipoprotein B will be determined from the DNA sequence of overlapping Agt10 apoB cDNA clones. The structure of the apoE deficient gene will be determined with conventional techniques and the function of the cloned genes will be measured using transient and stable eukarvotic cell expression systems. The synthesis and post translational modificaitons of apolipoproteins will be studied in intestinal cell lines. The importance of the segments of apolipoproteins involved in post translational modification will be determined by site directed mutagenesis. The cis-acting elements or transacting factors involved in the expression of apolipoprotein genes will be assessed by expression studies of appropriately mutagenized human apolipoprotein genes. The findings of the proposed studies would be very important from a public health standpoint. Abnormalities in lipoprotein metabolism contribute significantly to coronary atherosclerosis and heart disease. The development of atherosclerosis could be retarded if the molecular bases of the diseases which lead to it were known and tests were available to diagnose these diseases early in life. The proposed research will enhance our knowledge of new molecular aspects of lipoprotein metabolism which may be relevant to human diseases and will contribute towards better diagnoses and treatment of these conditions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL033952-07
Application #
3346380
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1984-09-01
Project End
1991-08-31
Budget Start
1990-09-01
Budget End
1991-08-31
Support Year
7
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Boston University
Department
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Drosatos, Konstantinos; Kypreos, Kyriakos E; Zannis, Vassilis I (2007) Residues Leu261, Trp264, and Phe265 account for apolipoprotein E-induced dyslipidemia and affect the formation of apolipoprotein E-containing high-density lipoprotein. Biochemistry 46:9645-53
Drosatos, Konstantinos; Sanoudou, Despina; Kypreos, Kyriakos E et al. (2007) A dominant negative form of the transcription factor c-Jun affects genes that have opposing effects on lipid homeostasis in mice. J Biol Chem 282:19556-64
Zannis, Vassilis I; Chroni, Angeliki; Krieger, Monty (2006) Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL. J Mol Med 84:276-94
Chroni, Angeliki; Duka, Adelina; Kan, Horng-Yuan et al. (2005) Point mutations in apolipoprotein A-I mimic the phenotype observed in patients with classical lecithin:cholesterol acyltransferase deficiency. Biochemistry 44:14353-66
Chroni, Angeliki; Kan, Horng-Yuan; Shkodrani, Adelina et al. (2005) Deletions of helices 2 and 3 of human apoA-I are associated with severe dyslipidemia following adenovirus-mediated gene transfer in apoA-I-deficient mice. Biochemistry 44:4108-17
Chroni, Angeliki; Kan, Horng-Yuan; Kypreos, Kyriakos E et al. (2004) Substitutions of glutamate 110 and 111 in the middle helix 4 of human apolipoprotein A-I (apoA-I) by alanine affect the structure and in vitro functions of apoA-I and induce severe hypertriglyceridemia in apoA-I-deficient mice. Biochemistry 43:10442-57
Kan, Horng-Yuan; Georgopoulos, Spiros; Zanni, Markella et al. (2004) Contribution of the hormone-response elements of the proximal ApoA-I promoter, ApoCIII enhancer, and C/EBP binding site of the proximal ApoA-I promoter to the hepatic and intestinal expression of the ApoA-I and ApoCIII genes in transgenic mice. Biochemistry 43:5084-93
Chroni, Angeliki; Liu, Tong; Gorshkova, Irina et al. (2003) The central helices of ApoA-I can promote ATP-binding cassette transporter A1 (ABCA1)-mediated lipid efflux. Amino acid residues 220-231 of the wild-type ApoA-I are required for lipid efflux in vitro and high density lipoprotein formation in vivo. J Biol Chem 278:6719-30
Zannis, Vassilis I; Liu, Tong; Zanni, Markella et al. (2003) Regulatory gene mutations affecting apolipoprotein gene expression: functions and regulatory behavior of known genes may guide future pharmacogenomic approaches to therapy. Clin Chem Lab Med 41:411-24
Kardassis, Dimitris; Roussou, Anastasia; Papakosta, Paraskevi et al. (2003) Synergism between nuclear receptors bound to specific hormone response elements of the hepatic control region-1 and the proximal apolipoprotein C-II promoter mediate apolipoprotein C-II gene regulation by bile acids and retinoids. Biochem J 372:291-304

Showing the most recent 10 out of 70 publications