Extracellular RNAs: Biomarkers for Cardiovascular Risk and Disease

描述（由申请人提供）： 心血管疾病（CVD）和中风是北美成人发病率和死亡率的两个主要原因，并且由常见CVD风险因素（包括高血压、糖尿病、肥胖、吸烟和血脂异常）的水平强烈决定。特定的细胞外RNA调节CVD发病机制的关键过程，几项小型人类研究将细胞外RNA与特定形式的CVD相关联。我们假设血浆RNA的表达随时间而变化，并受到暴露于CVD危险因素的持续时间和强度的影响，与亚临床动脉粥样硬化表型有关，因此将是CVD事件的有用预测因子。我们打算在急性冠状动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CVD和临床前CVD表型相关的细胞外RNA的诊断和预后效用。 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进行高产量血浆RNA提取以及高通量测序，以鉴定已知和尚未发现的细胞外循环RNA，从而开发一系列广泛的血浆来源的细胞外RNA生物标志物（包括miRNA、皮尔纳、非编码RNA）来筛选2914名参与FHS研究的参与者（后代检查8）。在申请的U3阶段，我们将通过在5年后筛选相同的个体（后代检查9），进一步评估循环RNA随时间的变化以及与CVD事件和疾病进展的关系。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CVD相关预后之间的关联。我们将进行探索性分析，以确定这些方法是否可以扩展到非CVD人群。最后，我们将与行业领导者合作，开发一种快速有效的细胞外RNA谱即时检测方法。 与疾病有关。

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.