Circulating cell-free microRNAs in atherogenesis

描述(申请人提供)：microRNAs(MiRNAs)是一类具有巨大生物学功能的新型非编码RNA。更重要的是，血液中发现了循环中的无细胞miRNAs。与我们最初的想法相反，由于与循环血液中的外切体等其他物质结合，无细胞miRNAs相对稳定。我们和其他研究小组的研究表明，这些循环中的无细胞miRNAs可以用作许多疾病的新生物标记物，包括癌症和心脏病。然而，在疾病条件下，这些循环中的无细胞miRNAs的来源和生物标记物之外的生物学作用目前尚不清楚。动脉粥样硬化仍然是导致发病率的主要原因，也是我们医疗保健系统的主要成本。这些循环中的无细胞miRNAs在动脉粥样硬化中的表达谱、来源和生物学作用目前尚不清楚。我们研究计划的长期目标是确定循环中无细胞miRNAs在动脉粥样硬化中的生物学作用。R21应用的目的是确定循环中无细胞miR-122在动脉粥样硬化形成中的潜在生物学作用。我们的假设是，动脉粥样硬化血液中的活来源无细胞miR-122增加。血液miR-122能够进入血管壁和血管细胞。循环中的无细胞miR-122不仅可以作为动脉粥样硬化的一种新的生物标志物，而且可以通过其直接的血管作用在动脉粥样硬化的形成中发挥重要作用。我们的假设得到了初步研究的支持。我们将通过以下两个具体目标进一步验证我们的假设：目标1是确定动脉粥样硬化血液中miR-122的水平，它进入体外培养的血管细胞的能力，它的生物学功能，以及涉及的机制。目的2在载脂蛋白E基因敲除小鼠体内检测miR-122的无细胞进入血管壁的能力、miR-122在动脉粥样硬化中的水平和表达分布、miR-122在动脉粥样硬化形成中的生物学作用及其可能的机制。这项拟议的研究具有很高的创新性。如果成功，它将为动脉粥样硬化提供一个全新的机制和一个新的治疗靶点，并可能创造一个新的科学范式：循环中的无细胞microRNAs在心血管疾病的发病机制中。此外，这项拟议的研究还可能提供一种新的血液中动脉粥样硬化的生物标志物。 公共卫生相关性：这些循环中的无细胞miRNAs在动脉粥样硬化形成中的生物学作用目前尚不清楚。本项目的目标是确定循环中的无细胞miR-122在动脉粥样硬化形成中的作用及其机制。

DESCRIPTION (provided by applicant): MicroRNAs (miRNAs) have emerged as a novel class of noncoding RNAs with tremendous biological functions. More importantly, circulating cell-free miRNAs are found in blood. In contrast to our original thought, the cell-free miRNAs are relatively stable due to binding with other materials such as exosomes in circulating blood. The studies from us and other groups have revealed that these circulating cell-free miRNAs can be used as novel biomarkers of many diseases including cancer and heart disease. However, the resources and the biological roles of these circulating cell-free miRNAs beyond biomarkers under disease conditions are currently unclear. Atherosclerosis is still the major cause of morbidity and the major cost in our healthcare system. The expression profiles, resources, and biological roles of these circulating cell-free miRNAs in atherosclerosis are currently unknown. The long-term goal of our research program is to determine the biological roles of circulating cell-free miRNAs in atherosclerosis. The goal of this R21 application is determine the potential biological roles of circulating cell-free miR-122 in atherogenesis. Our hypothesis is that the live-derived cell-free miR-122 is increased in atherosclerotic blood. The blood miR-122 is able to enter the vascular walls and vascular cells. The circulating cell-free miR-122 not only can be used as a novel biomarker for atherosclerosis, but can also play an important role in atherogenesis via its direct vascular effects. Our hypothesis is supported by our preliminary studies. We will further test our hypothesis by the following two specific aims: Aim 1 is to determine the levels of miR-122 in atherosclerotic blood, its capability to enter the vascular cells, its biological functions, and the mechanisms involved, in cultured vascular cells in vitro. Aim 2 is to determine the cell-free miR-122's capability to enter the vascular walls, the levels and expression distribution of miR-122 in atherosclerotic arteries, the biological role of miR-122 in atherogenesis, and its potential mechanisms in Apo E knockout mice in vivo. The proposed study is highly innovative. If successful, it will provide a totally new mechanism and a novel therapeutic target in atherosclerosis, and may create a novel scientific paradigm: "circulating cell-free microRNAs in the pathogenesis of cardiovascular diseases". In addition, the proposed study may also provide a novel biomarker of atherosclerosis in blood. PUBLIC HEALTH RELEVANCE: The biological roles of these circulating cell-free miRNAs in atherogenesis are currently unclear. The goal of this project is to determine the role of the circulating cell-free miR-122 in atherogenesis and its mechanisms.