Plasma levels of HDL are the strongest predictor of atherosclerosis risk and are related inversely to the disease incidence. Epidemiological studies suggest that HDL levels are in large part under genetic influence and that genetic factors are particularly important with regard to the inverse relationship of HDL with atherogenesis. Genetic regulation of metabolism of HDL and its major apoproteins A-I and A-II will be tested in subjects with very high or very low HDL levels and in their families by (1) study of their apo A-I and A-II gene regions for familial segregation of molecular genetic variation from other patients or controls, (2) study of their metabolism of HDL in selected subjects and kindreds by turnover techniques, (3) study of their HDL, and possibly of their cells, in an in vitro HDL-cell binding assay, (4) study of their post-heparin plasma and possibly of their adipose tissue and skeletal muscle, for endothelial lipase activity, (5) study of their LPL gene as appropriate probes become available, and (6) intercomparison of these data to attempt to define metabolic abnormalities in subjects with specific molecular genetic variance from normal. Also, human apo A-I, selectively altered at sites believed to relate to its rate of catabolism, will be produced by recombinant DNA in bacteria by site-specific mutagenesis. The catabolic rate of these altered apo A-I preparations will be tested in vivo in rabbits and compared to native human apo A-I both prepared from plasma and produced by recombinant methods.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL002034-03
Application #
3082482
Study Section
(SRC)
Project Start
1987-09-10
Project End
1992-09-09
Budget Start
1989-09-10
Budget End
1990-09-09
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Rockefeller University
Department
Type
Graduate Schools
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065