Extracellular RNAs: Biomarkers for Cardiovascular Risk and Disease

描述(由申请人提供)： 心血管疾病(CVD)和中风是北美成年人发病率和死亡率的两大主要原因，主要由高血压、糖尿病、肥胖、吸烟和血脂异常等常见心血管疾病危险因素的水平决定。特定的细胞外RNA调节CVD发病机制的关键过程，几项小型人类研究已将细胞外RNA与特定形式的CVD联系起来。我们推测，血浆RNA的表达随着时间的推移而变化，并受CVD危险因素暴露的时间和强度的影响，与亚临床动脉粥样硬化表型有关，因此将成为CVD事件的有用预测因子。我们打算在一个急性冠脉综合征住院样本的社区队列研究中，进一步探索和验证与心血管疾病和临床前心血管疾病表型相关的细胞外RNA的诊断和预后作用。为了实现这些目标，在我们研究的U2阶段，我们将使用优化的非商业分离方法提取高产量的血浆RNA，以及高通量测序来识别已知和尚未发现的细胞外循环RNA，从而开发一系列来自血浆的细胞外RNA生物标记物(包括miRNA、piRNA、非编码RNA)来筛选弗雷明翰心脏研究(FHS)研究(子代考试8)的2914名参与者。在应用程序的U3阶段，我们将通过5年后对相同的人进行筛查，进一步评估循环RNA随时间的变化以及与心血管事件和疾病进展的关系(后代检查9)。然后，我们将在TRACE-CORE(急性冠状动脉事件的转变和研究-结果研究和教育中心)的约400名参与者中检查细胞外RNA与心血管相关预后之间的关系。我们将进行探索性分析，以确定这些方法是否可以推广到非心血管疾病人群。最后，我们将与行业领先者合作，开发一种快速有效的细胞外RNA图谱护理点测试 与疾病相关的。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) and stroke are two of the leading causes of morbidity and mortality among adults in North America and are strongly determined by levels of common CVD risk factors including hypertension, diabetes, obesity, cigarette smoking, and dyslipidemia. Specific extracellular RNAs regulate key processes central to the pathogenesis of CVD and several small human studies have associated extracellular RNAs with specific forms of CVD. We postulate that the expression of plasma RNAs change over time and is influenced by the duration and intensity of exposure to CVD risk factors, relates to subclinical atherosclerosis phenotypes, and will therefore be useful predictors of incident CVD events. We intend to further explore and validate the diagnostic and prognostic utility of extracellular RNAs associated with CVD and preclinical CVD phenotypes in our community-based cohort study in a hospitalized sample with acute coronary syndromes. To accomplish these aims, in the U2 phase of our study we will use an optimized non-commercial isolation method for high-yield plasma RNA extraction as well as high-throughput sequencing to identify known and as-yet undiscovered extracellular circulating RNAs, thereby developing a broad panel of plasma-derived extracellular RNA biomarkers (including miRNA, piRNA, noncoding RNAs) to screen 2914 participants in the Framingham Heart Study (FHS) Study (Offspring Exam 8). In the U3 phase of the application, we will further evaluate changes in circulating RNAs over time and in relation to incident CVD and disease progression, by screening the same individuals 5 years later (Offspring Exam 9). We will then examine associations between extracellular RNAs and CVD-related prognosis in ~400 participants of TRACE-CORE (Transitions and Research in Acute Coronary Events - Center for Outcomes Research and Education). We will perform exploratory analyses to determine if these methods can be extended to non-CVD populations. Last, we will partner with industry leaders to develop a quick and effective point-of-care test for extracellular RNA profiles associated with disease.