Reversal of Heart Failure: Role of Vascular Recovery

项目摘要 心力衰竭是世界范围内发病率和死亡率的主要原因，目前估计影响650万人 仅在美国，成年人的医疗保健费用就高达210亿美元。本提案的目的是为了了解 心力衰竭恢复的机制。我们有临床证据表明心力衰竭的恢复涉及到 减少间质性心肌纤维化和增加微血管密度。我们的人类图书馆 左心室辅助装置（LVAD）植入/再植入的样本代表便利样本 检查恢复的机制。在这些患者中，LVAD植入（和心脏卸载） 从血液动力学力）促进心室功能的一些改善（如通过 超声心动图），其与减少的间质纤维化和增加的血管密度相关。基于 根据临床和临床前数据，我们假设心力衰竭的恢复（至少部分）是血管性的， 复苏血管恢复可能涉及间充质-内皮转化（MEEndoT），即， 心脏成纤维细胞（或其他间充质细胞）转分化为内皮细胞。而且我们 有证据表明，MEEndoT可能需要糖酵解开关，直接影响DNA的可及性和细胞 可塑性在我们的第一个目标中，我们将描述心力衰竭的生理、细胞和分子特征 在独特的小鼠模型中恢复。在第二个目标中，将分解的小鼠心脏的转录谱分析作为 以及LVAD植入前后获得的人体心脏组织将与生物信息学相结合 分析以预测心力衰竭恢复中的新基因。在我们的第三个目标中，我们将确认基因 在第一个目标中使用体外和体内功能获得或丧失研究发现的决定因素。此外，本发明还提供了一种方法， 我们将利用生物信息学来探索糖酵解开关在细胞命运转换和血管恢复中的作用 我们的RNAseq数据的分析，证实了细胞特异性和条件性获得或丧失功能的研究， 靶基因（如代谢途径）在体外和体内。该提案的目的是产生 关于心力衰竭恢复的基本见解，可能导致新的治疗策略。

PROJECT SUMMARY Heart failure is a major cause of morbidity and mortality worldwide, currently affecting an estimated 6.5 million adults in the US alone and contributing to $21 billion in health care costs. The aim of this proposal is to understand the mechanisms of heart failure recovery. We have clinical evidence that heart failure recovery involves a reduction in interstitial myocardial fibrosis and an increase in microvascular density. Our library of human samples from Left Ventricular Assist Device (LVAD) implantation/explantation represent a convenience sample to examine the mechanisms of recovery. In these patients, the LVAD implantation (and unloading of the heart from hemodynamic forces) promotes some improvement in ventricular function (as assessed by echocardiography) that is associated with decreased interstitial fibrosis and increased vascular density. Based on clinical and pre-clinical data, we hypothesize that recovery from heart failure is (at least in part) a vascular recovery. The vascular recovery may involve mesenchymal-to-endothelial transition (MEndoT), that is, the transdifferentiation of cardiac fibroblasts (or other mesenchymal cells) into endothelial cells. Furthermore, we have evidence that MEndoT may require a glycolytic switch that directly affects DNA accessibility and cellular plasticity. In our first aim, we will characterize the physiological, cellular, and molecular hallmarks of heart failure recovery in a unique mouse model. In the second aim, transcriptional profiling of disaggregated mouse hearts as well as human cardiac tissue obtained pre- and post-LVAD implantation will be combined with bioinformatics analyses to predict novel genes in heart failure recovery. In our third aim, we will confirm the genetic determinants discovered in the first aim using gain- or loss-of-function studies in vitro and in vivo. In addition, we will explore the role of the glycolytic switch in cell fate transitions and vascular recovery using bioinformatics analyses of our RNAseq data, confirmed with cell-specific and conditional gain- or loss-of-function studies of target genes (e.g. in metabolic pathways) in vitro and in vivo. The intent of this proposal is to generate fundamental insights regarding heart failure recovery that may lead to a new therapeutic strategy.