Role of DNA methylation in cardiac failure and recovery

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PROJECT SUMMARY/ABSTRACT Heart failure (HF) is a chronic, progressive and irreversible disorder that is associated with significant morbidity, mortality and expense. However, recovery of cardiac function has been reported in ~15% of HF patients on left ventricular assist devices (LVADs), which can be significant enough to allow for device explantation. Thus, the ability to potentiate cardiac recovery would be paradigm-shifting. Identification of factors associated with cardiac recovery will provide an opportunity to a) focus our efforts aimed at promoting recovery, b) gain insight into the mechanisms leading to disease progression and reversal, and c) discover new therapeutic targets. My goal in seeking a Mentored Research Career Development Award is to acquire the necessary training and experience to pioneer the novel field of epigenomics and genomics of HF by positioning myself as a pivotal translational integrator in the virtuous cycle of “bedside to bench research and back”. My clinical background along with the translational research training gained through this proposal, will allow me to orchestrate successful translational studies by prioritizing gene pathways of high clinical relevance for functional studies and by better standardizing and integrating clinical and genomic data. This proposal includes a discovery approach to understand the molecular bases for HF and cardiac recovery (Aim 1) and a predictive approach to design a multivariate model predictive of cardiac recovery (Aim 2). In Aim 1, we will focus on answering the questions “what gene pathways are dysregulated in HF” and “does LVAD therapy uniquely alter these gene pathways in responders vs non- responders” (Aim 1A), for which we will compare DNA methylation and gene expression from myocardium of HF and non-failing controls, followed by comparisons between pre- and post-LVAD within responders as compared to non-responders. Next, we will investigate the molecular mechanisms by which DNA methylation reprograms cardiac metabolism in cardiac recovery. We hypothesize that DNMT3a binds to, and methylates, specific genetic loci to alter gene expression involved in regulation of glycolysis and oxidative phosphorylation (Aim 1B). We will perform ChIP-qPCR of DNMT3a in a targeted manner of our already identified gene candidates (e.g. HADHA, etc.). In Aim 2, we will define the epigenetic predictors of cardiac recovery, by comparing DNA methylation and gene expression in responders and non-responders at the pre-LVAD timepoint, and will build a multivariable predictive model including clinical variables. The expertise of our multidisciplinary team, combined with formal didactics will provide the support needed to achieve my training aims, developing skills in: (1) design of genetic/epigenetic studies; (2) bioinformatics; and (3) professional development as a PI. In summary, our research will further our understanding of the mechanisms involved in HF and recovery and lay the foundation for the discovery of novel and personalized approaches to treat HF and improve patients’ outcomes. With completion of the training aims, I will be uniquely-positioned to pursue a career as an independent investigator with expertise in conducting sound genomic/epigenomic research in cardiac failure and recovery.