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.

项目概要/摘要 心力衰竭（HF）是一种慢性、进行性和不可逆的疾病，与显着的发病率相关， 死亡率和费用。然而，据报道约 15% 的左心衰患者心功能恢复 心室辅助装置（LVAD），其足够大以允许装置移植。因此， 增强心脏恢复的能力将是范式转变。识别与心脏相关的因素 复苏将提供一个机会：a）集中精力促进复苏，b）深入了解 导致疾病进展和逆转的机制，以及 c) 发现新的治疗靶点。我的目标是 寻求指导研究职业发展奖是为了获得必要的培训和经验 通过将自己定位为关键的转化者，开拓心力衰竭表观基因组学和基因组学的新领域 “临床到实验室研究并返回”良性循环中的集成者。我的临床背景以及 通过这个提案获得的转化研究培训将使我能够策划成功的转化研究 通过优先考虑与功能研究具有高度临床相关性的基因途径以及更好地标准化来进行研究 并整合临床和基因组数据。该提案包括一种发现方法来理解 心力衰竭和心脏恢复的分子基础（目标 1）以及设计多变量模型的预测方法 预测心脏恢复（目标 2）。在目标 1 中，我们将重点回答“什么基因途径 在 HF 中失调”和“LVAD 治疗是否独特地改变了反应者与非反应者中的这些基因通路 反应者”（目标 1A），为此，我们将比较 DNA 甲基化和心肌的基因表达 HF 和非失败对照，然后对响应者内 LVAD 前后进行比较 与无反应者相比。接下来，我们将研究DNA甲基化的分子机制。 在心脏恢复中重新编程心脏代谢。我们假设 DNMT3a 结合并甲基化， 改变参与糖酵解和氧化磷酸化调节的基因表达的特定基因位点 （目标 1B）。我们将以我们已确定的候选基因为目标，对 DNMT3a 进行 ChIP-qPCR （例如 HADHA 等）。在目标 2 中，我们将通过比较 DNA 来定义心脏恢复的表观遗传预测因子 在 LVAD 前时间点，对有反应者和无反应者的甲基化和基因表达进行分析，并将建立一个 包括临床变量的多变量预测模型。我们的多学科团队的专业知识相结合 正式的教学将提供实现我的培训目标所需的支持，培养以下方面的技能：(1) 设计 遗传/表观遗传学研究； (2)生物信息学； (3) 作为 PI 的专业发展。综上所述，我们的 研究将进一步加深我们对心力衰竭和恢复所涉及机制的理解并奠定基础 表彰发现治疗心力衰竭和改善患者预后的新颖且个性化的方法。和 完成培训目标后，我将处于独特的地位，可以从事独立调查员的职业生涯 拥有在心力衰竭和恢复方面进行健全的基因组/表观基因组研究的专业知识。

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