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.

项目概要：最近的工作表明，动脉剪切应力水平会诱导 miR-17-92 簇的成分拮抗 miR-92a 可增强动脉生成、改善内皮功能并预防血管体内有炎症。我们在令人兴奋的初步数据中表明，miR 17-92 的遗传丢失 EC 中的簇可增加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 的侧支、中和可改善后肢缺血后血流的功能恢复 (HLI) 并去抑制促进动脉生成的基因的表达。此外，由于剪切和 VEGF可以激活ERK，数据显示VEGF-A通过ERK1/2信号传导诱导miR-17-92簇该簇的成分在生理上抑制调节血管生成的基因表达。因此，这些数据意味着血流动力学和 VEGF 信号传导在 miR 17-92 簇上汇聚以进行微调 EC 中动脉生成和血管生成基因的表达。因此，我们假设 miR-92a 和 miR-19a 在通过抑制协同促进动脉重塑的基因表达来控制动脉重塑结构和功能性动脉生成。为了检验这一假设，提出以下具体目标： 1：利用遗传和药理学阐明 miR-92a 和 miR-19a/b 在动脉生成过程中的作用策略； 2：考察ERK与WNT信号通路串扰在调节中的重要性动脉发生和 3：在体外鉴定 EC 中 miR 92a 和 miR-19a/b 的独特和共同靶标以及体内，使用下一代测序技术。