Unraveling the genetic basis of common polygenic diseases, such as hypertension, diabetes and heart failure, will require fresh approaches to view how genes work together in groups rather than singly. In this proposal, we investigate gene network analysis as a promising new approach. Our goal is to identify specific expression patterns of gene modules, rather than single genes, which predict susceptibility to heart failure (HF). A network analysis of DNA microarray data typically groups 20,000 genes into 20-30 modules, each containing 10's to 100's of gene, drastically reducing number of possible candidates required to perform a gene network- based Gene Module Association Study (GMAS), which will be complementary to GWAS. To test the GMAS concept, we will use a systems genetics approach integrating DNA microarray analysis with physiological studies and computational modeling, to examine whether gene module expression patterns predict susceptibility to heart failure (HF) induced by cardiac stress. For this purpose, we will utilize a novel resource developed at UCLA, the Hybrid Mouse Diversity Panel (HMDP), consisting of 102 strains of inbred mice from which a common mouse cardiac modular gene network comprised of 20 gene modules has been constructed. Our preliminary findings reveal that different HMDP strains show considerable variability in both gene module expression patterns and phenotypic response to chronic cardiac stress (isoproterenol). Using biological and computational experiments, we will test the hypothesis that gene module expression patterns among HMDP strains represent different """"""""good enough solutions,"""""""" all of which are adequate for normal excitation-contraction- metabolism coupling, but have different abilities to adapt to chronic cardiac stress.
Three Specific Aims i ntegrating experimental and computational biology and combining discovery-driven, hypothesis-driven, and translational elements are proposed, towards the goal of relating HMDP results directly to human heart failure.

Public Health Relevance

Heart failure affects over 6 million Americans and is the most frequent cause of hospitalization among Medicare patients. Better understanding of the complex genetic factors predisposing to heart failure may lead to novel approaches aimed at preventing heart failure progression, thereby improving the quality of life and reducing mortality for patients with this dreaded disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL114437-01A1
Application #
8545516
Study Section
Special Emphasis Panel (ZRG1-VH-D (50))
Program Officer
Larkin, Jennie E
Project Start
2013-09-04
Project End
2017-05-31
Budget Start
2013-09-04
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$1,162,645
Indirect Cost
$360,758
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Norheim, Frode; Bjellaas, Thomas; Hui, Simon T et al. (2018) Genetic, dietary, and sex-specific regulation of hepatic ceramides and the relationship between hepatic ceramides and IR. J Lipid Res 59:1164-1174
Santolini, Marc; Romay, Milagros C; Yukhtman, Clara L et al. (2018) A personalized, multiomics approach identifies genes involved in cardiac hypertrophy and heart failure. NPJ Syst Biol Appl 4:12
Rees, Colin M; Yang, Jun-Hai; Santolini, Marc et al. (2018) The Ca2+ transient as a feedback sensor controlling cardiomyocyte ionic conductances in mouse populations. Elife 7:
Lin, Liang-Yu; Chun Chang, Sunny; O'Hearn, Jim et al. (2018) Systems Genetics Approach to Biomarker Discovery: GPNMB and Heart Failure in Mice and Humans. G3 (Bethesda) 8:3499-3506
Rosa-Garrido, Manuel; Chapski, Douglas J; Schmitt, Anthony D et al. (2017) High-Resolution Mapping of Chromatin Conformation in Cardiac Myocytes Reveals Structural Remodeling of the Epigenome in Heart Failure. Circulation 136:1613-1625
Pillai, Indulekha C L; Li, Shen; Romay, Milagros et al. (2017) Cardiac Fibroblasts Adopt Osteogenic Fates and Can Be Targeted to Attenuate Pathological Heart Calcification. Cell Stem Cell 20:218-232.e5
Gao, Chen; Wang, Yibin (2017) Untangle a Broken Heart via Janus Kinase 1. Circ Res 121:589-590
Seldin, Marcus M; Kim, Eric D; Romay, Milagros C et al. (2017) A systems genetics approach identifiesTrp53inp2as a link between cardiomyocyte glucose utilization and hypertrophic response. Am J Physiol Heart Circ Physiol 312:H728-H741
Norheim, Frode; Hui, Simon T; Kulahcioglu, Emre et al. (2017) Genetic and hormonal control of hepatic steatosis in female and male mice. J Lipid Res 58:178-187
Patterson, Michaela; Barske, Lindsey; Van Handel, Ben et al. (2017) Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration. Nat Genet 49:1346-1353

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