Role of DNA methylation in cardiac failure and recovery

DNA 甲基化在心力衰竭和恢复中的作用

• 批准号: 10641007
• 负责人: Omar Enrique Wever-Pinzon
• 金额: $ 19.87万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10641007
• 关键词: ASCL1 gene; Acceleration; Adult; Affect; Apical; Area; Back; Binding; Bioinformatics; Biological; Candidate Disease Gene; Cardiac; Cardiovascular system; Characteristics; Chronic; Clinical; Clinical Data; Clinical Investigator; DNA Methylation; DNA Methylation Regulation; DNMT3a; Data; Development; Devices; Diagnosis; Disease; Disease Progression; Epigenetic Process; Foundations; Gene Expression; Gene set enrichment analysis; Genes; Genetic; Genetic Transcription; Genomics; Glycolysis; Goals; Healthcare Systems; Heart; Heart failure; Image; K-Series Research Career Programs; Malignant Neoplasms; Mentors; Messenger RNA; Methods; Methylation; Modeling; Modification; Molecular; Molecular Analysis; Morbidity - disease rate; Myocardial; Myocardium; Output; Oxidative Phosphorylation; Pathogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Pattern; Population; Positioning Attribute; Promoter Regions; Publications; Recovery; Regulation; Reporting; Research; Research Personnel; Research Training; Role; Sampling; Severities; Standardization; Study models; Testing; Time; Tissues; Training; Transcriptional Regulation; Translational Research; Treatment Failure; Work; advanced disease; base; bench to bedside; bisulfite sequencing; candidate identification; career; clinical predictors; clinically relevant; design; epigenomics; exceptional responders; experience; gene function; genome sequencing; genomic data; genomic locus; heart function; heart metabolism; hemodynamics; implantation; improved; improved outcome; insight; left ventricular assist device; mortality; multidisciplinary; new technology; new therapeutic target; novel; novel strategies; novel therapeutics; personalized approach; personalized medicine; predictive modeling; programs; rational design; responders and non-responders; skills; sound; targeted treatment; transcriptome sequencing; translational study; whole genome

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.

项目总结/文摘

项目成果

Twelfth Interagency Registry for Mechanically Assisted Circulatory Support Report: Readmissions After Left Ventricular Assist Device.

• DOI: 10.1016/j.athoracsur.2021.12.011
• 发表时间: 2022-03
• 期刊: The Annals of thoracic surgery
• 作者: Shah P;Yuzefpolskaya M;Hickey GW;Breathett K;Wever-Pinzon O;Ton VK;Hiesinger W;Koehl D;Kirklin JK;Cantor RS;Jacobs JP;Habib RH;Pagani FD;Goldstein DJ
• 通讯作者: Goldstein DJ

Recovery With Temporary Mechanical Circulatory Support While Waitlisted for Heart Transplantation.

• DOI: 10.1016/j.jacc.2021.12.022
• 发表时间: 2022-03-08
• 期刊: Journal of the American College of Cardiology
• 影响因子: 24
• 作者: Topkara VK;Sayer GT;Clerkin KJ;Wever-Pinzon O;Takeda K;Takayama H;Selzman CH;Naka Y;Burkhoff D;Stehlik J;Farr MA;Fang JC;Uriel N;Drakos SG
• 通讯作者: Drakos SG