Atherosclerosis is the major cause of morbidity and mortality in the United States. Plasma levels of LDL and cholesterol are major risk factors to its development. In humans, the liver primarily controls plasma LDL and cholesterol levels through LDL receptor-mediated catabolism and cholesterol/lipoprotein biosynthesis. The milieu of the atherosclerotic plaque, enriched with cytokines and growth factors, may be the key to unravelling and controlling atherosclerosis. The goals of this research project are to define at the cellular and molecular level the role of microenvironment derived soluble mediators in regulating receptor-dependent and independent uptake, synthesis, and accumulation of cholesterol at the vessel wall, as well as systemically, in a hepatoblastoma-derived cell line. The mechanisms regulating functional activity and gene expression of the LDL receptor, scavenger receptor, and HMG-CoA reductase enzyme will be defined in the cells comprising the atherosclerotic plaque and correlated with SMC and macrophage cholesterol accumulation. Key mediators of vascular cholesterol trafficking will be compared to inflammatory and vascular cell-derived cytokine regulation of liver cholesterol metabolism. Understanding, and thus ultimately coordinating vascular cell cholesterol physiology with liver cholesterol catabolism is the long-term aim.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Physician Scientist Award (K11)
Project #
5K11HL002738-03
Application #
3087867
Study Section
Research Manpower Review Committee (MR)
Project Start
1992-07-01
Project End
1997-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Arizona
Department
Type
Schools of Medicine
DUNS #
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Stopeck, A T; Nicholson, A C; Mancini, F P et al. (1993) Cytokine regulation of low density lipoprotein receptor gene transcription in HepG2 cells. J Biol Chem 268:17489-94