Congestive heart failure is a complex disease involving multiple genetic and environmental factors. Three years ago, the laboratories of Dr. Yibin Wang, a molecular biologist with expertise in heart failure, and Dr. Aldons Lusis, a geneticist working in the area of cardiovascular disease, joined forces to perform a genetic screen in a hybrid mouse diversity panel (HMDP) to identify genes contributing to common forms of heart failure. For the past two years, this work has been supported by a multi- PI R21. This support enabled us to complete the preliminary screen and identified over 30 genome-wide significant loci harboring genes contributing to different aspects of cardiac pathologies induced by chronic stimulation of the ?-adrenergic agonist isoproterenol (ISO), including hypertrophy, fibrosis, and cardiac dysfunction and remodeling. Moreover, gene expression profiles were obtained from all HMDP mouse hearts in control mice and following ISO treatment. These rich datasets containing genetic information detailed cardiac phenotype parameters and comprehensive cardiac transcriptome profiles from 107 inbred strains of mice will allow us to harness the power of genetics and systems approaches to identify novel molecular pathways contributing to the specific aspects of cardiac pathology during heart failure. Indeed, we observed a dramatic diversity of heart failure phenotypes among all HMDP strains following ISO stimulation and discovered a number of genetic loci and gene modules with significant association with cardiac hypertrophy and fibrosis. These data support the overall hypothesis that common genetic variants have a major contribution to the pathogenesis of heart failure. Uncovering the mechanistic basis of these newly discovered HF associated genes and their interactions via systems approach is the overarching goal of this proposal. Specifically, in Aim 1, we will extend our systems studies to discover genes and gene modules significantly associated with cardiac pathology induced by chronic angiotensin II treatment (AngII). We will identify unique and common genes involved in ?AR vs. ?AR-specific pathogenesis in heart.
In Aim 2, we will investigate the molecular mechanisms underlying a candidate gene associated with heart failure, Miat, that encodes a long-non-coding (lnc)RNA with a previously unknown function in heart.
In Aim 3, we will investigate the mechanism and functional role of Abcc6, a GWAS candidate gene, in stress induced cardiac fibrosis. These studies will reveal the underlying genetic contributions to specific features of heart failure, and the uncovered novel pathology associated genes and their interaction should provide new insights to the mechanism of the disease.

Public Health Relevance

The great complexity of heart failure has made direct human studies, such as genome-wide association studies, difficult. The causal genes which we identify in mice may have significant contribution to common forms of CHF in human populations, and the revealed pathways will help us to better understand the disease mechanism. This knowledge is expected to lead to improved diagnosis and treatment based on the genetic makeup of the individuals.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL123295-01
Application #
8722898
Study Section
Special Emphasis Panel (ZRG1-CVRS-P (02))
Program Officer
Wang, Lan-Hsiang
Project Start
2014-04-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$657,392
Indirect Cost
$230,514
Name
University of California Los Angeles
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Sun, Haipeng; Olson, Kristine C; Gao, Chen et al. (2016) Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure. Circulation 133:2038-49
Wang, Zhihua; Zhang, Xiao-Jing; Ji, Yan-Xiao et al. (2016) The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy. Nat Med 22:1131-1139
Lusis, Aldons J; Seldin, Marcus M; Allayee, Hooman et al. (2016) The Hybrid Mouse Diversity Panel: a resource for systems genetics analyses of metabolic and cardiovascular traits. J Lipid Res 57:925-42
Rau, Christoph D; Parks, Brian; Wang, Yibin et al. (2015) High-Density Genotypes of Inbred Mouse Strains: Improved Power and Precision of Association Mapping. G3 (Bethesda) 5:2021-6
Wang, Zhihua; Wang, Yibin (2015) Dawn of the Epi-LncRNAs: new path from Myheart. Circ Res 116:235-6
Cattin, Marie-Elodie; Wang, Jessica; Weldrick, Jonathan J et al. (2015) Deletion of MLIP (muscle-enriched A-type lamin-interacting protein) leads to cardiac hyperactivation of Akt/mammalian target of rapamycin (mTOR) and impaired cardiac adaptation. J Biol Chem 290:26699-714
Brænne, Ingrid; Civelek, Mete; Vilne, Baiba et al. (2015) Prediction of Causal Candidate Genes in Coronary Artery Disease Loci. Arterioscler Thromb Vasc Biol 35:2207-17
Rau, Christoph D; Wang, Jessica; Avetisyan, Rozeta et al. (2015) Mapping genetic contributions to cardiac pathology induced by Beta-adrenergic stimulation in mice. Circ Cardiovasc Genet 8:40-9
Neelankavil, Jacques; Rau, Christoph D; Wang, Yibin (2015) The Genetic Basis of Coronary Artery Disease and Atrial Fibrillation: A Search for Disease Mechanisms and Therapeutic Targets. J Cardiothorac Vasc Anesth 29:1328-32
Rau, Christoph D; Lusis, Aldons J; Wang, Yibin (2015) Genetics of common forms of heart failure: challenges and potential solutions. Curr Opin Cardiol 30:222-7

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