The role of microRNAs during arteriogenesis

microRNA 在动脉生成过程中的作用

• 批准号: 253160555
• 负责人: Dr. Silvia Fischer
• 金额: --
• 依托单位: Biochemisches Institut
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/253160555?language=en
• 关键词: role; microRNAs; during; arteriogenesis

The fluid shear stress (FSS)-induced remodeling of pre-existing collateral arterioles into fully functional conductance arteries is termed "arteriogenesis".It has been shown that FFS, which is exerted on endothelial cells, leads to changes in the expression profile of microRNA (miRs), which in turn alters morphology as well as function of endothelial cells under flow conditions. miRs are small non-conding RNAs, which regulate gene expression post-transcriptionally either through inhibition of translation or due to RNA decay. In a pilot study we identified a differential expression of miR-24, miR-143, miR-146a and miR-195 in growing collateral arteries by microarray screening, quantitative RT-PCR, and in situ hybridization.Through the current project the relevance of these miRs for arteriogenesis will be evaluated in vitro and in a mouse model. In preliminary experiments, blockage of those miRs by local intra-arterial injection of antimiRs (single-standed complementary RNA oligonucleotides) after ligation of the femoral artery showed that mice, which were treated with antimiR-143, have a significantly reduced perfusion recovery. In addition they suffer from increased necrosis and autoamputation of hind limbs, which results in a higher lethality. While elucidating the cause of the drastic consequences of antimiR-143 application, the possibility of mir-143 being a key regulator and the presence of unwanted side effects of therapeutic miRNA modulation will be accounted for. The present study will clarify the differentiation between specific antimiR effects (blockage of target mRNA) during collateral growth and unspecific systemic antimiR effects. On one hand, the regulation and molecular interaction of miRNAs and their contribution to arteriogenic key processes will be assessed, on the other hand, possible influence of antimiR application on vascular hemostasis will be examined. It has been shown that ribonucleases are not inert structures; they rather display toxic, apoptotic pro-coagulatory or pro-inflammatory activity. It will be analyzed in detail if this is also true for antimiRs.

流体剪切力（fluid shear stress，FSS）作用于血管内皮细胞，可导致内皮细胞microRNA（microRNA，miRs）表达谱的改变，进而改变内皮细胞的形态和功能。miR是小的非编码RNA，其通过抑制翻译或由于RNA降解而在转录后调节基因表达。在一项初步研究中，我们通过微阵列筛选、定量RT-PCR和原位杂交等方法鉴定了miR-24、miR-143、miR-146 a和miR-195在生长中的侧支动脉中的差异表达，通过本项目，我们将在体外和小鼠模型中评估这些miR与动脉生成的相关性。在初步实验中，通过在股动脉结扎后局部动脉内注射antimiR（单链互补RNA寡核苷酸）来阻断这些miR显示，用antimiR-143处理的小鼠具有显著降低的灌注恢复。此外，它们患上增加的坏死和后肢自截肢，这导致更高的致死率。在阐明antimiR-143应用的严重后果的原因的同时，mir-143作为关键调节剂的可能性以及治疗性miRNA调节的不希望的副作用的存在将被解释。本研究将阐明侧支生长过程中特异性antimiR效应（靶mRNA的阻断）与非特异性系统性antimiR效应之间的差异。一方面，将评估miRNAs的调控和分子相互作用及其对动脉形成关键过程的贡献，另一方面，将检查antimiR应用对血管止血的可能影响。已经表明，核糖核酸酶不是惰性结构;它们显示毒性、凋亡促凝或促炎活性。如果这也适用于抗miR，将进行详细分析。