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：
9894484
负责人：
Saumya Das
金额：
$ 96.07万
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/9894484
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 Risk stratification Role Sampling Signal Pathway Signal Transduction Structure 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 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 (HF) 的治疗取得了重要进展，但超过 50% 的患者在 5 年内死亡首次入院时就被诊断出心力衰竭，心力衰竭仍然是发病率、死亡率和死亡率的主要原因美国的医疗保健支出。预计到 2030 年，心力衰竭的患病率将增至 46%，对心力衰竭发病机制的新机制见解以及中断这一进程的策略仍然是一个巨大的未满足的问题临床需要。我的研究重点是外泌体或细胞外囊泡 (EV) 及其货物的作用 RNA (EV-RNA) 作为新型功能生物标志物。我们发现并验证了血浆 RNA 特征与人类心力衰竭表型相关，例如心肌梗塞后的不良结构重塑，纤维化和心律失常性猝死。我们已经证明许多血浆 RNA 被隔离在电动汽车内，是一种新颖的细胞间通信模式。重要的是，许多 EV-RNA 发生了变化在心脏组织中同时调节可能是心力衰竭发病机制的复杂信号通路。这这项工作提供了一个独特的机会来开发 i) 新型临床有用的生物标志物，以改善风险分层心力衰竭患者； ii) 中断不良重塑过程的新治疗靶点。我现在寻求利用过去 5 年开发的工具和平台来移动 EV 和 EV-RNA 使用灵活的 R35 授权机制向新的方向发展。我寻求广泛地解决以下问题未满足需求的领域。 1. 提高血浆的性能（包括预后/预测准确性和方差系数）通过在生物样本库血浆中经过验证的平台上更具体地测量 EV-RNA 来获得 RNA 生物标志物来自仔细表型的心力衰竭和心肌梗死后患者的样本。 2. 确定从具有不同表型的人类 HF 样本中分离出来的 EV 的功能作用细胞培养（iPSC 衍生的 CM）和芯片上器官模型 3. 利用新型外泌体追踪小鼠模型 (ExoMap) 确定功能外泌体靶向小鼠缺血模型中心肌细胞和其他心肌细胞的后果和非缺血性 HF 使用单细胞核 RNAseq。 4. 识别 EV 释放/摄取的小分子调节因子，以操纵 EV 介导的信号传导小鼠模型。 5. 利用新发现的细胞 RNA 生物标志物开发新型条件 siRNA 疗法针对心脏肥大、自噬和纤维化。 R35机制提供的灵活性和自由度将让我能够追求这些高风险高回报旨在解决该领域关键差距的实验，也将为致力于指导提供时间下一代心血管疾病研究人员。