Elevated levels of plasma high-density lipoprotein cholesterol (HDL) protect against cardiovascular disease, which is the leading cause of death in the United States. Identifying the genes involved in the regulation of HDL may reveal some novel genes and pave the way for the development of future therapies. The Jackson Laboratory's ENU mutagenesis program has identified an excellent collection of 16 mutant mice, all in the C57BL/6 background, that have elevated HDL. These are a great resource for understanding HDL regulation and for discovering novel genes. Strains have already been established for each of these 16 different mutant mice. We now propose to identify the mutations underlying these 16 strains with elevated HDL and have the following aims: 1. Map all 16 HDL mutations to a coarse chromosomal position, 2. Identify the gene and the causal mutation, and 3. Test each mutant to determine whether the elevated HDL protects against atherosclerosis susceptibility. Mapping ENU mutations for quantitative traits is complicated because of the presence of quantitative trait loci (QTL) caused by natural polymorphisms for the phenotype of interest between the mutated strain and the strain used for the mapping crosses. We have designed strategies to avoid this problem in ENU mutant mapping by first crossing to a closely related strain, which will have few polymorphisms and thus few QTL with C57BL/6. When the chromosomal location of a mutant is known, fine mapping is carried out with a cross to a chromosomal substitution strain, which will have the same C57BL/6 background and differ only in the chromosome of interest. This strategy should allow us to successfully map and identify these HDL mutants.
The genes that will be identified and characterized in these studies will give us a better understanding of the regulation of HDL cholesterol levels. The biological pathways that will be uncovered by identifying novel genes should lead to new therapeutic targets for preventing and treating heart disease.
|Ananda, Guruprasad; Takemon, Yuka; Hinerfeld, Douglas et al. (2014) Whole-genome sequence of the C57L/J mouse inbred strain. G3 (Bethesda) 4:1689-92|
|Choi, Seungbum; Aljakna, Aleksandra; Srivastava, Ujala et al. (2013) Decreased APOE-containing HDL subfractions and cholesterol efflux capacity of serum in mice lacking Pcsk9. Lipids Health Dis 12:112|
|Ackert-Bicknell, Cheryl; Paigen, Beverly; Korstanje, Ron (2013) Recalculation of 23 mouse HDL QTL datasets improves accuracy and allows for better candidate gene analysis. J Lipid Res 54:984-94|
|Nawijn, Martijn C; Piavaux, Benoit J A; Jeurink, Prescilla V et al. (2011) Identification of the Mhc region as an asthma susceptibility locus in recombinant congenic mice. Am J Respir Cell Mol Biol 45:295-303|
|Leduc, Magalie S; Lyons, Malcolm; Darvishi, Katayoon et al. (2011) The mouse QTL map helps interpret human genome-wide association studies for HDL cholesterol. J Lipid Res 52:1139-49|