Based on the incompleteness of our understanding of High Density Lipoprotein (HDL) metabolism the focus of this proposal is the identification of new genes involved in the metabolism of this lipoprotein through genome-wide expression screens. Mouse cDNA arrays containing >5000 mouse genes will be used to identify genes whose expression is altered in the liver and adrenals of several transgenic and knockout lines of mice chosen based on their characterized abnormalities in HDL metabolism. This will initially include transgenic and knockout mice for apolipoprotein A-I (apo A-I), Scavenger Receptor class b1 (sr- bi), Hepatic lipase (HL), and Lecithin Cholesterol Acyl Transferase (LCAT). A basic assumption in these studies is that alterations in the expression of genes known to be involved in HDL metabolism will affect the expression of other genes also participating in the metabolism of this lipoprotein. The novel genes identified from these studies will be prioritized for further biological characterization based on a variety of parameters including: level of expression change, clustering of expression patterns between mice of different HDL mutant genotypes, and sequence or expression pattern similarities to other genes known to participate in lipoprotein metabolism. The function of a limited number of novel """"""""HDL candidate"""""""" genes (approximately 10) will be assessed each year through their over-expression in transgenic mice coupled with careful analysis of the consequence of transgene over-expression over-expression on lipoprotein metabolism. In these studies we will be utilizing a combination of new technologies and previously developed experimental substrates to address the fundamental question of what genes are directly or indirectly involved in the metabolism of HDL in vivo.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063897-02
Application #
6351598
Study Section
Genome Study Section (GNM)
Program Officer
Applebaum-Bowden, Deborah
Project Start
2000-02-05
Project End
2004-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
2
Fiscal Year
2001
Total Cost
$446,733
Indirect Cost
Name
Lawrence Berkeley National Laboratory
Department
Type
Organized Research Units
DUNS #
078576738
City
Berkeley
State
CA
Country
United States
Zip Code
94720
Callow, Matthew J; Rubin, Edward M (2002) Expression profiling and comparative sequence derived insights into lipid metabolism. Curr Opin Lipidol 13:173-9
Qiu, Y; Cavelier, L; Chiu, S et al. (2001) Human and mouse ABCA1 comparative sequencing and transgenesis studies revealing novel regulatory sequences. Genomics 73:66-76
Callow, M J; Dudoit, S; Gong, E L et al. (2000) Microarray expression profiling identifies genes with altered expression in HDL-deficient mice. Genome Res 10:2022-9
Friddle, C J; Koga, T; Rubin, E M et al. (2000) Expression profiling reveals distinct sets of genes altered during induction and regression of cardiac hypertrophy. Proc Natl Acad Sci U S A 97:6745-50