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

基本信息

  • 批准号:
    10641007
  • 负责人:
  • 金额:
    $ 19.87万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
  • 影响因子:
    0
  • 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:
  • 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
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Omar Enrique Wever-Pinzon其他文献

Omar Enrique Wever-Pinzon的其他文献

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{{ truncateString('Omar Enrique Wever-Pinzon', 18)}}的其他基金

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
  • 财政年份:
    2020
  • 资助金额:
    $ 19.87万
  • 项目类别:
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:
    10455474
  • 财政年份:
    2020
  • 资助金额:
    $ 19.87万
  • 项目类别:
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
  • 财政年份:
    2020
  • 资助金额:
    $ 19.87万
  • 项目类别:

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