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: 10227189
• 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/10227189
• 关键词: ASCL1 gene; 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; Lead; Malignant Neoplasms; Mentors; Messenger RNA; Methods; 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; 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; 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.

项目摘要/摘要 心力衰竭（HF）是一种慢性，进行性和不可逆转的疾病，与明显的发病率相关， 死亡率和费用。但是，据报道，左侧约有15％的HF患者的心脏功能恢复 心室辅助设备（LVADS），可以足够重要，可以允许设备外观。那， 潜在的心脏恢复能力将是范式转移。识别与心脏相关的因素 恢复将为a）集中精力旨在促进恢复的机会提供机会，b）洞悉 导致疾病进展和逆转的机制，c）发现新的治疗靶标。我的目标 寻求指导的研究职业发展奖是要获得必要的培训和经验 通过将自己定位为关键翻译，开创了HF的表观基因组学和基因组学的新颖领域 在“床头到板凳研究和背部”的虚拟周期中的集成商。我的临床背景以及 通过该建议获得的翻译研究培训将使我能够精心策划成功的翻译 通过优先考虑高临床相关性的基因途径来进行功能研究的研究，并通过更好地标准化 并整合临床和基因组数据。该建议包括一种发现方法来了解 HF和心脏恢复的分子碱基（AIM 1）和设计多元模型的预测方法 预测心脏恢复（AIM 2）。在AIM 1中，我们将专注于回答“什么基因途径” 在HF中失调”和“ DOS LVAD疗法在反应者中唯一改变了这些基因途径 响应者”（AIM 1A），为此，我们将比较来自心肌的DNA甲基化和基因表达 HF和非运输控件，然后在响应者中进行比较 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与甲基化和甲基化结合， 特定的遗传局部体改变了与糖酵解和氧化磷酸化调节有关的基因表达 （AIM 1B）。我们将以我们已经确定的基因候选者的目标方式执行DNMT3A的CHIP-QPCR （例如哈达等）。在AIM 2中，我们将通过比较DNA来定义心脏恢复的表观遗传预测指标 响应者和非反应者的甲基化和基因表达在LVAD之前的时间点上，并将建立一个 多变量预测模型，包括临床变量。我们的多学科团队的专业知识合并 使用正式的教学方法将提供实现我的培训目标所需的支持，并在以下方面发展技能：（1）设计 遗传/表观遗传学研究； （2）生物信息学； （3）专业发展作为PI。总而言之，我们的 研究将进一步了解HF和恢复涉及的机制，并奠定基础 为了发现新颖和个性化的方法来治疗HF并改善患者的结果。和 培训目标的完成，我将被唯一地置于独立调查员的职业 具有在心脏衰竭和恢复方面进行声音基因组/表观基因组研究方面的专业知识。