Functional role and therapeutic targeting of exosomes and extracellular RNA biomarkers in heart failure

外泌体和细胞外 RNA 生物标志物在心力衰竭中的功能作用和治疗靶向

基本信息

批准号：
10417068
负责人：
Saumya Das
金额：
$ 97.7万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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：
2020-06-01 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10417068
关键词：
Address Area Autophagocytosis Biological Markers Biology Cardiac Cardiac Myocytes Cardiovascular Diseases Cell Culture Techniques Cell physiology Cells Cessation of life Clinical Complex Diagnosis Disease Fibrosis Grant Health Expenditures Heart Hypertrophy Heart failure Hospitalization Human Interruption Measures Mediating Mentors Modeling Morbidity - disease rate Mus Myocardial Infarction Nuclear Pathogenesis Patients Performance Phenotype Plasma Play Prevalence Process RNA Research Research Personnel Role Sampling Signal Pathway Signal Transduction Time Tissues United States Work biobank clinical biomarkers clinically actionable exosome experimental study extracellular extracellular vesicles flexibility high reward high risk improved induced pluripotent stem cell insight intercellular communication mortality mouse model new therapeutic target next generation novel novel therapeutics organ on a chip prognostic risk stratification small molecule therapeutic siRNA therapeutic target tool transcriptome sequencing uptake vesicular release

项目摘要

Despite important advances in the treatment of heart failure (HF), >50% of patients die within 5 years of diagnosis at their first hospital admission, and HF remains a leading cause of morbidity, mortality and healthcare expenditure in the United States. With the prevalence of HF expected to increase to 46% by 2030, novel mechanistic insight into HF pathogenesis and strategies to interrupt this progression are a large unmet clinical need. My research has focused on the role of exosomes or extracellular vesicles (EVs) and their cargo RNAs (EV-RNAs) as novel functional biomarkers. We have discovered and validated plasma RNA signatures that correlate with human HF phenotypes such as adverse structural remodeling after myocardial infarction, fibrosis and sudden arrhythmic death. We have shown that many of these plasma RNAs are sequestered within EVs and are a novel mode of intercellular communication. Importantly, many of these EV-RNAs change in parallel in cardiac tissue, modulating complex signaling pathways that may underlie HF pathogenesis. This work affords a unique opportunity to develop i) novel clinically useful biomarkers for improved risk stratification of HF patients; and ii) novel therapeutic targets to interrupt the adverse remodeling process. I now seek to leverage the tools and platforms developed over the past 5 years to move the EV and EV-RNA field in new directions using the flexible R35 grant mechanism. I seek to broadly address the following broad areas of unmet need. 1. Improve the performance (including prognostic/predictive accuracy and coefficient of variance) of plasma RNA biomarkers by more specifically measuring EV-RNAs on validated platforms in biorepository plasma samples from carefully-phenotyped HF and post-MI patients. 2. Determine a functional role for EVs isolated from human HF samples with varied phenotypes in simplified cell culture (iPSC-derived CMs) and organ-on-chip models 3. Leverage a novel murine model of exosome tracking (ExoMap) mouse to determine the functional consequences of exosome targeting in cardiomyocytes and other cardiac cells in murine models of ischemic and non-ischemic HF using single cell nuclear RNAseq. 4. Identify small molecule regulators of EV release/uptake to manipulate EV-mediated signaling in these murine models. 5. Leverage newly identified cellular RNA biomarkers to develop novel conditional siRNA therapeutics that target cardiac hypertrophy, autophagy and fibrosis. The flexibility and latitude afforded by the R35 mechanism will allow me to pursue these high-risk high-reward experiments that seek to address critical gaps in this field and will also provide time for devoting to mentoring of the next generation of cardiovascular disease investigators.

尽管心力衰竭治疗（HF）的重要进展，但> 50％的患者在5年内死亡在他们的第一次住院时诊断，HF仍然是发病率，死亡率和美国的医疗支出。随着HF的患病率预计到2030年增加到46％，对HF发病机理和中断这种进展的策略的新机械洞察力是很大的未经临床需求。我的研究集中在外泌体或细胞外囊泡（EV）及其货物的作用上 RNA（EV-RNA）作为新型功能生物标志物。我们发现并验证了等离子体RNA签名与人HF表型相关的，例如心肌梗塞后不良结构重塑，纤维化和突然的心律失常。我们已经表明，其中许多等离子体RNA都是隔离的在电动汽车中，是一种新颖的细胞间通信方式。重要的是，其中许多EV-RNA改变了在心脏组织中并行，调节可能是HF发病机理的复杂信号通路。这工作为开发i）新型临床有用的生物标志物提供了一个独特的机会，以改善风险分层 HF患者； ii）中断不良重塑过程的新型治疗靶标。我现在寻求利用过去5年中开发的工具和平台来移动EV和EV-RNA 使用灵活的R35赠款机制在新方向上进行字段。我试图广泛地解决以下广泛的问题未满足的领域。 1。提高等离子体的性能（包括差异的预后/预测精度和方差系数） RNA生物标志物通过更具体地测量生物座等等离子体的验证平台上的EV-RNA 来自精心型的HF和MI后患者的样品。 2。确定在简化中具有不同表型的人类HF样品中分离出的电动汽车的功能作用细胞培养（IPSC衍生的CMS）和芯片器官模型 3。利用一种新型外泌体跟踪（Exomap）小鼠的鼠模型来确定功能在缺血模型中心肌细胞和其他心脏细胞中外泌体靶向的后果使用单细胞核RNASEQ和非缺血性HF。 4。确定EV释放/摄取的小分子调节剂，以操纵EV介导的信号传导鼠模型。 5。利用新鉴定的细胞RNA生物标志物发展出新的条件siRNA疗法靶心肥大，自噬和纤维化。 R35机制提供的灵活性和纬度将使我能够追求这些高风险的高潮试图解决该领域关键差距的实验，还将为精力指导提供时间下一代心血管疾病研究者