miR 92/19 cluster in the ERK context

ERK 背景下的 miR 92/19 簇

基本信息

批准号：
10192387
负责人：
William C Sessa
金额：
$ 52.01万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-10 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10192387
关键词：
Arteries Atherosclerosis Blood flow Cells Complement Complex Data Endothelial Cells Endothelium Equilibrium Exposure to Gene Expression Gene Expression Profile Genes Genetic Growth Factor Heart Heart Diseases High-Throughput Nucleotide Sequencing Hindlimb Immunoprecipitation In Vitro Individual Inflammation Mediators Ischemia Isolated limb perfusion Knockout Mice Leg Limb structure MAPK1 gene MAPK3 gene Mediating Messenger RNA MicroRNAs Modeling Molecular Molecular Target Mus Pathologic Pathway interactions Patients Peripheral Vascular Diseases Pharmacology Physiological Process Public Health RNA Recovery of Function Reporter Research Role Seeds Shapes Signal Transduction Structure Technology Testing Transgenic Mice Vascular Diseases Vascular Endothelial Growth Factors Vascular remodeling WNT Signaling Pathway Work aged angiogenesis arterial remodeling arteriole beta catenin crosslink density experimental study genomic data hemodynamics improved in vivo limb ischemia mechanotransduction next generation sequencing overexpression prevent response shear stress synergism vascular inflammation

项目摘要

Project Summary: Recent work has shown that arterial levels of shear stress induce components of the miR-17-92 cluster and antagonizing miR-92a enhances arteriogenesis, improves endothelial function and prevents vascular inflammation in vivo. We have shown in exciting preliminary data that the genetic the loss of the miR 17-92 cluster in EC increases arteriogenesis in the hearts and limbs of mice. Remarkably, in aged mice with defective collateralization, neutralization of miR-19a/b improves functional recovery of blood flow after hindlimb ischemia (HLI) and de-represses the expression of genes that promote arteriogenesis. In addition, since both shear and VEGF can activate ERK, data has shown that VEGF-A induces the miR-17-92 cluster via ERK1/2 signaling and components of the cluster physiologically repress gene expression that regulates angiogenesis. Thus, these data imply that hemodynamics and VEGF signaling converge on the miR 17-92 cluster to fine tune arteriogenic and angiogenic gene expression in EC. Thus, we hypothesize that miR-92a and miR-19a work in concert to govern arterial remodeling by repressing the expression of genes that synergize to promote structural and functional arteriogenesis. To test this hypothesis, the following specific aims are proposed: 1: Elucidate the role of miR-92a and miR-19a/b during arteriogenesis using genetic and pharmacological strategies; 2: Examine the importance of ERK crosstalk with the WNT signaling pathway in regulating arteriogenesis and 3: Identify the unique and common targets of miR 92a and miR-19a/b in EC both in vitro and in vivo, using next generation sequencing technology.

项目摘要：最近的工作表明，剪切应力的动脉水平诱导miR-17-92簇的成分拮抗miR-92a可以增强动脉生成，改善内皮功能并防止血管体内炎症。我们在令人兴奋的初步数据中表明，miR的遗传丧失17-92 EC中的聚类增加了小鼠心脏和四肢的动脉生成。值得注意的是，在有缺陷的老年小鼠中 MIR-19A/B的抵押，中和改善后肢缺血后血流的功能恢复（HLI）并取消抑制促进动脉生成的基因的表达。此外，既然剪切和 VEGF可以激活ERK，数据表明VEGF-A通过ERK1/2信号诱导miR-17-92群集簇的成分生理抑制了调节血管生成的基因表达。因此，这些数据表明，血液动力学和VEGF信号在miR上收敛17-92群集以微调 EC中的动脉生成和血管生成基因表达。因此，我们假设miR-92a和miR-19a在通过抑制协同促进基因的表达来控制动脉重塑以促进动脉重塑结构和功能性动脉生成。为了检验这一假设，提出了以下具体目的：1：使用遗传学和药理学阐明miR-92a和miR-19a/b在动脉生成过程中的作用策略； 2：检查ERK串扰与Wnt信号通路在调节中的重要性动脉生成和3：确定MiR 92a和miR-19a/b在EC中的独特和常见靶标都在体外和体内，使用下一代测序技术。