miR 92/19 cluster in the ERK context

ERK 背景下的 miR 92/19 簇

• 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
• 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

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： 最近的研究表明，动脉水平的剪切应力诱导miR-17-92簇的成分， 拮抗miR-92 a可增强动脉生成，改善内皮功能并防止血管生成。 体内炎症。我们已经在令人兴奋的初步数据中表明，miR 17-92的丢失是遗传学上的， EC中的簇增加小鼠心脏和四肢中的动脉生成。值得注意的是，在有缺陷的老年小鼠中 miR-19 a/B的侧支化、中和改善后肢缺血后血流的功能恢复 (HLI)并解除对促进动脉生成的基因表达的抑制。此外，由于剪切和 VEGF可以激活ERK，数据显示VEGF-A通过ERK 1/2信号传导诱导miR-17-92簇 并且簇的组分在生理上抑制调节血管生成的基因表达。因此，在本发明中， 这些数据表明，血流动力学和VEGF信号传导集中在miR 17-92簇上， EC中动脉生成和血管生成基因的表达。因此，我们假设miR-92 a和miR-19 a在 通过抑制协同促进动脉重塑的基因表达， 结构和功能性动脉生成。为了检验这一假设，提出了以下具体目标：1： 利用遗传学和药理学方法阐明miR-92 a和miR-19 a/B在动脉形成中的作用 策略; 2：检查ERK与WNT信号通路的串扰在调节细胞凋亡中的重要性。 动脉生成和3：体外鉴定EC中miR 92 a和miR-19 a/B的独特和共同靶点 和在体内，使用下一代测序技术。