Cardiac Exosomes in myocardial Ischemic injury

项目总结/摘要 缺血性心脏病，全球死亡的主要原因，每年4750亿美元，也是最昂贵的 在美国，这种疾病是高度遗传的。缺血启动特定的生物过程， 基因、转录和翻译变异。特别是，通过非编码RNA（ncRNA）的调节， 人类基因组中的重要组成部分，在肌细胞的生物学中起着重要作用， 缺血细胞外囊泡（EV）是一种新型的细胞间通讯调节因子， 生物信息，包括蛋白质，脂质和ncRNA。EV中含有的ncRNA，即 细胞外RNA（exRNA）包括microRNA和其他类型的小RNA和lncRNA，其中一些 已被证明受到压力源的调节，并介导受体细胞的功能效应。因此，在本发明中， exRNA作为治疗分子和疾病的生物标志物提供了巨大的潜力。 我们已经建立了一个独特的人体组织样本库，超过230例心肌缺血患者 同时进行心肺转流（CPB）心脏手术。CPB是一种应用人体模型， 缺血，因为它与心脏生物标志物证实的强制性缺血性心肌损伤相关 释放，因此与非卧床心肌梗死具有共性。利用这一资源， 作为我们NHLBI奖的一部分，在过去的四年里，我们研究了mRNA的差异表达，lncRNA， 缺血性人类左心室心肌中的microRNA，使我们处于一个理想的位置来研究 exRNA在心肌缺血损伤中意义 我们现在建议通过检查急性动态变化来进一步探索各种短和长ncRNA的作用。 缺血时ncRNA的变化。因此，我们将描述ncRNA转录组的特征。 人和小鼠心脏，在人的各种非缺血和缺血时间点检查exRNA， 小鼠，测试表达的数量性状基因座（eQTL），并在大量心脏外科手术患者中进行验证。 患者此外，我们将使用缺血小鼠模型来确定动态调节的exRNA是否在缺血小鼠中表达。 特别存在于心肌细胞衍生的EV中，这将为未来的介入治疗提供框架。 基因研究。 这项研究的结果将确定遗传变异、改变的ncRNA表达和 人心肌组织中的心肌损伤及其相关的ncRNA外周生物标志物。这些ncRNA 生物标志物可以具有直接的临床影响，并促进生物学理解，诊断和治疗。 人类心肌损伤的治疗。

PROJECT SUMMARY / ABSTRACT Ischemic heart disease, the leading cause of mortality worldwide and at $475 billion/year also the costliest disease in the US, is highly heritable. Ischemia initiates specific biological processes that are highly dependent on genetic, transcriptional, and translational variation. In particular, regulation by noncoding RNAs (ncRNA), crucial components in the human genome, play a significant role in the biology of myocytes undergoing ischemia. Extracellular vesicles (EV) are emerging as new regulators of cell-to-cell communication carrying biological information, including proteins, lipids, and ncRNAs. The ncRNAs contained in EV, namely extracellular RNAs (exRNA), include microRNAs and other types of small RNAs and lncRNAs, some of which have been shown to be regulated by stressors and mediate functional effects in their recipient cells. Thus, exRNA offer tremendous potential as therapeutic molecules and biomarkers of disease. We have built a unique human tissue sample bank of over 230 patients experiencing myocardial ischemia while undergoing cardiac surgery with cardiopulmonary bypass (CPB). CPB is an applied human model of ischemia, as it is associated with obligatory ischemic myocardial injury evidenced by cardiac biomarker release, and therefore shares commonality with ambulatory myocardial infarction. Using this resource and as part of our NHLBI award, in the past four years we examined mRNA differential expression, lncRNAs, and microRNAs in ischemic human left ventricular myocardium, putting us in an ideal position to study the significance of exRNA in myocardial ischemic injury. We now propose to further explore the role of various short- and long ncRNAs by examining acute dynamic changes in ncRNAs in response to ischemia. Therefore, we will characterize the ncRNA transcriptome in the human and mouse heart, examine exRNA at various non-ischemic and ischemic time points in humans and mice, test for expressed quantitative trait loci (eQTL), and validate in a large population of cardiac surgical patients. Furthermore, we will use an ischemic mouse model to determine if the dynamically regulated exRNAs are present specifically in cardiomyocyte-derived EVs which will provide the framework for future interventional genetic studies. The results of this study will define the link between genetic variation, altered ncRNA expression and myocardial injury in human myocardial tissue and its associated ncRNA peripheral biomarkers. These ncRNA biomarkers can have an immediate clinical impact and advance the biological understanding, diagnosis and therapy of myocardial injury in humans.