Program Director/Principal Investigator {Last, First, Middle): P a i g e n , B e v e r l y J PROJECT SUMMARY (See instnjctions}: Heart disease is the major cause of death in industrialized societies. Lifestyle changes and the many drugs available to reduce LDL cholesterol have done a great deal to reduce heart disease, and the major avenue to further therapeutic progress lies in learning how to raise HDL, a major protection against heart disease. The mouse is an excellent model for finding HDL genes because the quantitative trait loci (QTL) for HDL in mouse and human are found in concordant locations. In the extension period we will test the candidacy of Grin3a, Etv6, the 5 genes on Chr 19, and the candidate genes from the B6xC57L cross. The first step is to obtain and test knockout models for each of them. After the generation, these models will first be tested for differences in HDL cholesterol levels. When a difference is observed, we will obtain gene expression profiles from liver, adipose tissue, and macrophages. These profiles will direct us toward the pathway through which the candidate gene impacts HDL metabolism. Once these pathways are identified we will hypothesize the role of the gene within the pathway and design appropriate experiments to test the hypothesis.

Public Health Relevance

The major goal is to identify the genes and pathways that affect HDL cholesterol, which provides protection against the leading cause of death, heart disease. Identifying these HDL genes will uncover novel drug targets, and understanding the pathways of HDL regulation will elucidate the drug targets likely to have the greatest impact on HDL. Raising HDL is predicted to decrease heart disease incidence.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL077796-14
Application #
9303428
Study Section
Special Emphasis Panel (NSS)
Program Officer
Liu, Lijuan
Project Start
2014-07-01
Project End
2019-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
14
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609
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Paigen, Beverly; Currer, Joanne M; Svenson, Karen L (2016) Effects of Varied Housing Density on a Hybrid Mouse Strain Followed for 20 Months. PLoS One 11:e0149647
Yuan, Rong; Gatti, Daniel M; Krier, Rebecca et al. (2015) Genetic Regulation of Female Sexual Maturation and Longevity Through Circulating IGF1. J Gerontol A Biol Sci Med Sci 70:817-26
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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
Srivastava, Ujala; Paigen, Beverly J; Korstanje, Ron (2012) Differences in health status affect susceptibility and mapping of genetic loci for atherosclerosis (fatty streak) in inbred mice. Arterioscler Thromb Vasc Biol 32:2380-6
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Leduc, Magalie S; Blair, Rachael Hageman; Verdugo, Ricardo A et al. (2012) Using bioinformatics and systems genetics to dissect HDL-cholesterol genetics in an MRL/MpJ x SM/J intercross. J Lipid Res 53:1163-75
Hageman, Rachael S; Leduc, Magalie S; Korstanje, Ron et al. (2011) A Bayesian framework for inference of the genotype-phenotype map for segregating populations. Genetics 187:1163-70

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