tRNA片段—非编码小RNA基因调控网络对脑卒中后血管新生的影响及其机制研究

缺血性脑卒中治疗的关键是尽快恢复缺血区的血供，全面理解脑卒中后血管新生调控机制是研发高效促进治疗性血管新生技术的关键前提。最新研究发现由tRNA特异性剪切而来的tRNA片段（tRFs）具有强大的基因调控功能。我们在前期研究中对脑卒中大鼠脑组织进行了深度测序分析，发现脑缺血后tRNA-Val和 tRNA-Gly来源为主的tRFs丰度明显增加；实验还表明这类tRFs可显著抑制内皮细胞的增殖、迁移及成管能力，同时伴有Dicer酶表达显著下调。结合我们前期研究结果, 我们推测存在一条以tRFs、Dicer和miRNAs等非编码小RNA构成的新的基因调控网络并参与了脑卒中后血管新生的调控。本项目拟深入探讨tRFs、Dicer及其miRNAs等在血管新生过程的变化规律及相互调控关系，明确tRFs等小RNA基因表达调控网络对血管新生的影响和作用途径，进一步阐明脑卒中后血管新生的分子调控机制。

The recovery of blood supply as soon as possible is the key point for the treatment of ischemic stroke. Understanding of the molecular mechanism of post-ischemic angiogenesis comprehensively is the most important prerequisite for promoting therapeutic angiogenesis. The latest studies indicated that the tRNA-deriverd fragments (tRFs) participated in diverse gene regulation system and are widely involved in a series of pathophysiological processes. Our preliminary study showed that the expression of tRFs-derived from tRNAVal and tRNAGly were strikingly up-regulated in the rat brain 24 hours after ischemia induction as determined by deep sequencing and bioinformatics analysis. Overexpression of these tRFs significantly inhibited endothelial cell proliferation, migration and tube formation. The expression of Dicer was significantly reduced in response to the up-regulation of the tRFs. Combined with previous reports that tRFs regulated the expression of target genes by binding to the RNA binding protein YBX1, we hypothesized tRFs, Dicer and microRNAs work as a new gene regulatory networks and participate in regulation of the post-stroke angiogenesis. In this project, we will investigate the function of tRFs-Dicer-miRNA network in angiogenesis and clarify the molecular mechanism by which tRFs regulates post-ischemic angiogenesis.