Lipoprotein lipase (LPL) enzyme plays a pivitol role in lipid metabolism by hydrolyzing triglyceride (TG) rich lipoprotein particles. Many diseases, including coronary heart disease (CHD), atherosclerosis and obesity seem to be directly or indirectly related to abnormalities in LPL function. A Hind lll polymorphism in intron 8 of the LPL gene has been shown to be associated with plasma TG and HDL-cholesterol levels and with the risk of CHD. However, the biological mechanism behind this association is unknown. Previous studies have suggested that the intron 8 sequence, which encompasses the Hind lll site as well as intron 9 and non-coding exon 10 of the LPL gene, contain regulatory elements important for LPL transcription and translation. In this proposal we will determine if the nucleotide change in intron 8 by itself is responsible for the effect by disrupting an intronic enhancer element (Aim 1) and what is the role of the 3' region (intron 8, intron 9, exon 10) in regulating LPL transcription (Aim 2). In addition, we have identified a putative insulin response element (IRE) in non-coding exon 10 of the human LPL gene following sequence comparison of LPL genes from various species. The putative IRE sequence was targeted for mutation detection and we identified a 5 bp deletion mutation. We propose to characterize this new mutation further by performing functional and molecular studies (Aim 3). The proposed molecular and functional studies will characterize the functional significance of the LPL Hind lll and exon 10 mutations and may lead to identification and characterization of LPL regulatory elements in intragenic and 3 untranslated region of the gene. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL070169-02
Application #
6698838
Study Section
Special Emphasis Panel (ZRG1-CCVS (01))
Program Officer
Applebaum-Bowden, Deborah
Project Start
2003-01-24
Project End
2006-12-31
Budget Start
2004-01-15
Budget End
2004-12-31
Support Year
2
Fiscal Year
2004
Total Cost
$345,430
Indirect Cost
Name
University of Pittsburgh
Department
Genetics
Type
Schools of Public Health
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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