Apolipoproteins are components of lipoproteins that circulate in the blood and lymph, and mediate the transport and metabolism of lipids between various tissues. The regulation of the synthesis of these proteins is not well understood. The overall objective of this proposal is to characterize the molecular elements involved in the regulation of the expression of two human apolipoprotein gene complexes. The first gene complex is composed of the apo-E, apo-C-I, and apo-C-I' genes. The second complex is composed of the apo-A-IV, apo-C-III, and apo-A-I genes. The proposed studies are aimed at determining the sequence elements associated with these genes that control their expression. These control regions will be employed to identify, isolate, and characterize the intracellular components with which they interact. In particular, possible regulatory regions associated with the apo-E gene that mediate the response of the gene to intracellular cholesterol levels as well as inflammatory agents will be investigated. The structural and regulatory relationships of the apo-C-I and apo-C-I' genes will be determined. The regulation of the apo-A-IV gene in response to metabolic mediators will be characterized. Preliminary results from our laboratory indicate that multiple regulatory factors will be involved in determining the mechanisms of apolipoprotein gene expression. These studies are directed towards understanding the control mechanisms responsible for the synthesis of their mRNAs. Knowledge of this regulation should facilitate an understanding of the role of these apolipoproteins in circulating lipoproteins and their involvement in the pathogenesis of cardiovascular diseases such as atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL037063-02
Application #
3352601
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1986-07-01
Project End
1991-06-30
Budget Start
1987-07-01
Budget End
1988-06-30
Support Year
2
Fiscal Year
1987
Total Cost
Indirect Cost
Name
J. David Gladstone Institutes
Department
Type
DUNS #
047120084
City
San Francisco
State
CA
Country
United States
Zip Code
94158
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Harris, Faith M; Tesseur, Ina; Brecht, Walter J et al. (2004) Astroglial regulation of apolipoprotein E expression in neuronal cells. Implications for Alzheimer's disease. J Biol Chem 279:3862-8
Huang, Yadong; Weisgraber, Karl H; Mucke, Lennart et al. (2004) Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer's disease. J Mol Neurosci 23:189-204
Grehan, S; Allan, C; Tse, E et al. (2001) Expression of the apolipoprotein E gene in the skin is controlled by a unique downstream enhancer. J Invest Dermatol 116:77-84

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