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.
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.
|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|
|Monte, Emma; Rosa-Garrido, Manuel; Karbassi, Elaheh et al. (2016) Reciprocal Regulation of the Cardiac Epigenome by Chromatin Structural Proteins Hmgb and Ctcf: IMPLICATIONS FOR TRANSCRIPTIONAL REGULATION. J Biol Chem 291:15428-46|
|Gao, Chen; Wang, Yibin (2016) Positive Role for a Negative Calcineurin Regulator in Cardiac Hypertrophy. Hypertension 67:841-2|
|Weiss, James N; Garfinkel, Alan; Karagueuzian, Hrayr S et al. (2015) Perspective: a dynamics-based classification of ventricular arrhythmias. J Mol Cell Cardiol 82:136-52|
|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|
|BrÃ¦nne, 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|
Showing the most recent 10 out of 23 publications