MicroRNA-29b and Endothelial Function

MicroRNA-29b 和内皮功能

• 批准号: 8963009
• 负责人: MINGYU LIANG
• 金额: $ 52.26万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-04 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8963009
• 关键词: Animal Model; Animals; Arteries; Biological; Biological Availability; Blood Vessels; Characteristics; Data; Development; Diabetes Mellitus; Disease; Endothelium; Event; Future; Gene Expression; Gene Targeting; Genes; Genetically Modified Animals; Goals; Grant; Health; Human; Individual; Knock-out; Knowledge; Maintenance; Mediating; Methods; MicroRNAs; Microvascular Dysfunction; Modeling; Molecular; Morbidity - disease rate; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Phenotype; Physicians; Physiological; Prevalence; Process; Production; Proteins; Protocols documentation; RNA; Rattus; Regulation; Regulatory Pathway; Research Personnel; Resistance; Role; Scientist; Techniques; Testing; Untranslated RNA; Vascular Diseases; Vasodilation; arteriole; clinically relevant; db/db mouse; diabetic patient; endothelial dysfunction; experience; human NOS3 protein; innovation; knockout gene; novel; novel strategies; public health relevance; transcriptome sequencing; translational approach; volunteer

 DESCRIPTION (provided by applicant): Microvascular endothelial dysfunction precedes the development of vascular disease and portends future adverse vascular events. Endothelial dysfunction is readily identified by a characteristic loss of nitric oxide (NO) bioavailability, whch results from the dysregulation of a wide variety of proteins and molecular pathways. However, we lack important knowledge of how these proteins and molecules are coordinately regulated. MicroRNAs have been demonstrated to act as "master" regulators of physiological or disease processes by coordinately targeting multiple genes involved in the process. However, the role of microRNAs in endothelial dysfunction, especially in the context of diabetes, remains largely unexplored. We have obtained preliminary data suggesting a homeostatic level of vascular miR-29b is critical for the maintenance of normal microvascular NO bioavailability and endothelium-dependent vasodilation in humans and animal models. Conversely, in type 2 diabetes mellitus, a disease typified by reduced microvascular NO bioavailability and microvascular morbidity, miR-29b could restore NO bioavailability and endothelium- dependent vasodilation. MiR-29b's impact on NO bioavailability appears to arise from its coordinated effects on several genes that alter NO bioavailability at multiple levels of regulation. We propose in this application to investigate the novel role of miR-29b in microvascular endothelium- dependent vasodilation and NO bioavailability in health and in type 2 diabetes and identify the mechanisms mediating these effects of miR-29b. The proposed project will employ a highly translational approach that combines functional studies of a newly developed knockout rat model with studies of intact human vessels obtained from well-phenotyped volunteers. We will also employ newly developed methods for identifying target genes and molecular pathways involved in the effect of miR-29b. Specifically, we will test the hypothesis that endogenous miR-29b is critical to maintaining normal endothelium-dependent vasodilation and NO bioavailability in resistance vessels in healthy humans and animals in Aim 1. Aim 2 studies will test the hypothesis that miR-29b can restore endothelium-dependent vasodilation and NO bioavailability in resistance vessels from T2DM patients and db/db mice. The molecular mechanisms underlying the role of miR-29b in endothelium-dependent vasodilation and NO bioavailability will be examined in Aim 3. The study will be carried out by a team of experienced researchers led by a physician scientist and a basic scientist who possess complementary expertise ideally suited for the proposed project. Successful completion of the project will reveal novel mechanisms regulating endothelial function and demonstrate their clinical relevance.

 描述(申请人提供)：微血管内皮功能障碍是血管疾病发展的先兆，预示着未来的不良血管事件。内皮功能障碍很容易被识别为典型的一氧化氮(NO)生物利用度的丧失，这是由于多种蛋白质和分子途径的失调造成的。然而，我们缺乏关于这些蛋白质和分子是如何协调调节的重要知识。已经证明，microRNAs通过协调靶向参与生理或疾病过程的多个基因，充当生理或疾病过程的“主控”调节器。然而，microRNAs在内皮功能障碍中的作用，特别是在糖尿病的背景下，在很大程度上仍未被探索。我们已经获得的初步数据表明，在人类和动物模型中，血管miR-29b的动态平衡水平对于维持正常的微血管、NO生物利用度和内皮依赖性血管扩张至关重要。相反，在2型糖尿病中，以微血管无生物利用度和微血管发病率减少为典型特征的疾病，miR-29b可以恢复无生物利用度和内皮依赖性血管扩张。MIR-29b对NO生物利用度的影响似乎源于它对几个基因的协同作用，这些基因在多个调控水平上改变了NO的生物利用度。在这项应用中，我们建议研究miR-29b在微血管内皮依赖性血管扩张中的新作用，以及在健康和2型糖尿病中的NO生物利用度，并确定miR-29b介导这些作用的机制。拟议的项目将采用高度翻译的方法，将新开发的基因敲除大鼠模型的功能研究与从表型良好的志愿者获得的完整人类血管的研究结合起来。我们还将使用新开发的方法来识别与miR-29b作用相关的目标基因和分子途径。具体地说，在目标1中，我们将测试内源性miR-29b对维持健康人和动物阻力血管的正常内皮依赖性血管扩张和无生物利用度至关重要的假设。目的2研究将测试这一假设，即miR-29b可以恢复T2 DM患者和db/db小鼠的阻力血管的内皮依赖性血管扩张和无生物利用度。目标3将研究miR-29b在内皮依赖性血管扩张中的作用以及无生物利用度的分子机制。这项研究将由一名内科科学家和一名基础科学家领导的经验丰富的研究人员团队进行，他们拥有互补的专业知识，非常适合拟议的项目。该项目的成功完成将揭示调节内皮功能的新机制，并展示其临床意义。