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

• 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
• 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

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，但仍有>50%的患者在治疗后5年内死亡。 在首次入院时诊断，HF仍然是发病、死亡和死亡的主要原因。 美国的医疗保健支出。预计到2030年，HF的患病率将增加到46%， 对HF发病机制的新的机制见解和中断这种进展的策略是一个很大的未满足的 临床需要我的研究主要集中在外泌体或细胞外囊泡（EV）及其货物的作用 RNA（EV-RNA）作为新的功能性生物标志物。我们已经发现并验证了血浆RNA特征 与人类HF表型相关的疾病，如心肌梗死后的不良结构重塑， 纤维化和猝死。我们已经证明，许多这些血浆RNA被隔离， 在EV内，并且是细胞间通信的新模式。重要的是，这些EV-RNA中的许多都发生了变化， 在心脏组织中平行，调节可能是HF发病机制基础的复杂信号通路。这 工作提供了一个独特的机会，以开发i）新的临床有用的生物标志物，用于改善风险分层 的HF患者;和ii）新的治疗目标，以中断不良重塑过程。 我现在寻求利用过去5年开发的工具和平台， 字段在新的方向使用灵活的R35授权机制。我希望广泛地讨论以下问题 未满足需求的领域。 1.提高血浆的性能（包括预后/预测准确性和变异系数） 通过在生物储存血浆中的经验证平台上更特异性地测量EV-RNA的RNA生物标志物 来自仔细分型的HF和MI后患者的样本。 2.确定从具有不同表型的人HF样本中分离的EV的功能作用， 细胞培养（iPSC衍生的CM）和器官芯片模型 3.利用新型外泌体追踪小鼠模型（ExoMap）来确定功能性 外泌体靶向心肌细胞和其他心肌细胞在缺血性心脏病小鼠模型中的结果 和使用单细胞核RNAseq的非缺血性HF。 4.鉴定EV释放/摄取的小分子调节剂以操纵这些细胞中EV介导的信号传导。 鼠模型。 5.利用新鉴定的细胞RNA生物标志物开发新的条件性siRNA疗法， 靶向心脏肥大、自噬和纤维化。 R35机制所提供的灵活性和自由度将使我能够追求这些高风险高回报的目标。 旨在解决这一领域的关键差距的实验，也将提供时间用于指导 下一代的心血管疾病研究者。