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: 10055603
• 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/10055603
• 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; 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.

项目总结/摘要 心力衰竭（HF）是一种慢性、进行性和不可逆的疾病， 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），其可能足够重要以允许装置重新定位。因此 增强心脏恢复的能力将是一种范式转变。心脏病相关因素的识别 复苏将提供一个机会，a）集中我们的努力，旨在促进复苏，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 寻求导师研究职业发展奖是为了获得必要的培训和经验 通过将自己定位为一个关键的翻译， 在“床边到实验室研究再回来”的良性循环中，我的临床背景沿着着 通过本提案获得的翻译研究培训，将使我能够成功地策划翻译 通过优先考虑与功能研究高度临床相关的基因途径， 以及整合临床和基因组数据。该提案包括一种发现方法， HF和心脏恢复的分子基础（目标1）和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，我们将重点回答以下问题： 在HF中失调”以及“LVAD治疗是否独特地改变了反应者与非反应者的这些基因途径 反应者”（目的1A），为此，我们将比较来自心肌的DNA甲基化和基因表达， HF和非衰竭对照组，随后比较应答者中LVAD前后的差异， 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DNMT 3a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遗传位点 (Aim 1B）。我们将以我们已经鉴定的候选基因的靶向方式对DNMT 3a进行ChIP-qPCR (e.g. HADHA等）。在目标2中，我们将通过比较DNA， 在前LVAD时间点，应答者和非应答者的甲基化和基因表达，并将建立一个 包括临床变量的多变量预测模型。我们多学科团队的专业知识， 正式的教学法将提供所需的支持，以实现我的培训目标，发展技能：（1）设计 遗传学/表观遗传学研究;（2）生物信息学;（3）作为PI的专业发展。总之，我们的 研究将进一步加深我们对HF和康复机制的理解， 用于发现治疗HF和改善患者结局的新颖和个性化方法。与 完成培训目标后，我将有能力从事独立调查员的职业 具有在心力衰竭和恢复中进行合理的基因组/表观基因组研究的专业知识。