The study of the regulation and expression of apo(a) has vital clinical and scientific significance. Elevated plasma levels of Lp(a), demonstrated to account for about 25% of premature myocardial infarctions, are now recognized as a major inherited risk factor for atherosclerosis. Lp(a) can be thought of as a cholesterol-rich low density lipoprotein bound to a plasminogen-like protein called apolipoprotein(s) (apo(a)). It is thought that Lp(a) causes atherosclerosis by both proatherogenic and prothrombotic mechanisms. There is a remarkable, (nearly one-thousand fold), interindividual variation of plasma levels of Lp(a). The major locus that determines plasma levels of Lp(a) is the apo(a) locus, and we will test the hypothesis that most of the control of expression of apo(a) resides in regulatory regions located at the 5' end of the gene. The 5' flanking region of the apo(a) gene will be cloned and sequenced. The transcription start site of apo(a) mRNA and the promoter region of the apo(a) gene will be identified. Regulatory elements in the promoter region will be defined by means such as identification of DNA consensus sequence, reverse transcript synthesis, mobility shift analysis, DNase footprinting and site directed mutagenesis. In vitro effects of putative control sequences will be analyzed using transient expression in reporter gene systems. The in vivo effects of sequence variation will also be studied. A multi-pronged approach will be applied to determine sequence variants in genomic DNA obtained from large numbers of patients with extremes of levels of Lp(a). Cosegregation studies will be performed. The Lipid Clinic at UCSF provides a pool of ethnically diverse men and women for study.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL002761-02
Application #
3083163
Study Section
Research Training Review Committee (RTR)
Project Start
1992-07-01
Project End
1996-06-30
Budget Start
1993-07-01
Budget End
1994-06-30
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143