miR 92/19 cluster in the ERK context

项目总结： 最近的工作表明，动脉切应力水平诱导了miR-17-92簇的成分 拮抗miR-92a可促进动脉生成，改善内皮功能，防止血管 体内的炎症。我们已经在令人兴奋的初步数据中表明，miR 17-92的丢失是基因 EC中的簇会增加小鼠心脏和四肢的动脉生成。值得注意的是，在患有缺陷的老年小鼠中 侧支、中和miR-19a/b促进后肢缺血后血流功能恢复 (HLI)并抑制促进动脉形成的基因的表达。此外，由于剪切和 血管内皮生长因子可以激活ERK，有数据表明，血管内皮生长因子A通过ERK1/2信号途径诱导miR-17-92簇 该簇的组件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血管内皮生长因子信号在miR 17-92簇上聚合以进行微调 动脉和血管生成基因在EC中的表达。因此，我们假设miR-92a和miR-19a在 Concert通过抑制协同促进基因的表达来管理动脉重塑 结构动脉和功能动脉的形成。为了验证这一假设，提出了以下具体目标：1： 从遗传学和药理学角度阐明miR-92a和miR-19a/b在动脉形成中的作用 策略：2：研究ERK与WNT信号通路在调节中的重要性 动脉形成和3：确定血管内皮细胞中miR 92a和miR-19a/b的独特和共同靶点 在体内，使用下一代测序技术。

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.