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Temporal brain microRNA expression changes in a mouse model of neonatal hypoxic–ischemic injury
Pediatric Research ( IF 3.1 ) Pub Date : 2021-08-31 , DOI: 10.1038/s41390-021-01701-5
Eric S Peeples 1 , Namood-E Sahar 1 , William Snyder 1 , Karoly Mirnics 2, 3, 4
Affiliation  

Background

Neonatal hypoxic–ischemic brain injury (HIBI) results in significant morbidity and mortality despite current standard therapies. MicroRNAs (miRNAs) are a promising therapeutic target; however, there is a paucity of data on endogenous miRNA expression of the brain after HIBI during the primary therapeutic window (6–72 h after injury).

Methods

Postnatal day 9 mouse pups underwent unilateral carotid ligation+hypoxia (HIBI), sham surgery+hypoxia, or sham surgery+normoxia (controls). miRNA sequencing was performed on the ipsilateral brain of each of the three groups plus the contralateral HIBI brain at 24 and 72 h after injury. Findings were validated in eight key miRNAs by quantitative polymerase chain reaction.

Results

Hypoxia resulted in significant differential expression of 38 miRNAs at both time points. Mir-2137, -335, -137, and -376c were significantly altered by neonatal HIBI at 24 and 72 h, with 3 of the 4 demonstrating multiphasic expression (different direction of differential expression at 24 versus 72 h).

Conclusions

Our global assessment of subacute changes in brain miRNA expression after hypoxia or HIBI will advance research into targeted miRNA-based interventions. It will be important to consider the multiphasic miRNA expression patterns after HIBI to identify optimal timing for individual interventions.

Impact

  • This study is the first to comprehensively define endogenous brain microRNA expression changes outside of the first hours after neonatal hypoxic–ischemic brain injury (HIBI).

  • Mir-2137, -335, -137, and -376c were significantly altered by neonatal HIBI and therefore deserve further investigation as possible therapeutic targets.

  • The expression profiles described will support the design of future studies attempting to develop miRNA-based interventions for infants with HIBI.

  • At 24 h after injury, contralateral HIBI miRNA expression patterns were more similar to ipsilateral HIBI than to controls, suggesting that the contralateral brain is not an appropriate “internal control” for miRNA studies in this model.



中文翻译:


新生儿缺氧缺血性损伤小鼠模型颞脑 microRNA 表达变化


 背景


尽管采用目前的标准疗法,新生儿缺氧缺血性脑损伤(HIBI)仍会导致显着的发病率和死亡率。 MicroRNA (miRNA) 是一个有前途的治疗靶点;然而,关于 HIBI 后主要治疗窗口(损伤后 6-72 小时)期间大脑内源性 miRNA 表达的数据很少。

 方法


出生后第 9 天的小鼠幼崽接受单侧颈动脉结扎+缺氧(HIBI)、假手术+缺氧或假手术+常氧(对照)。损伤后 24 小时和 72 小时对三组各组的同侧大脑以及对侧 HIBI 大脑进行 miRNA 测序。通过定量聚合酶链反应在八个关键 miRNA 中验证了研究结果。

 结果


缺氧导致 38 个 miRNA 在两个时间点的表达显着差异。 Mir-2137、-335、-137 和 -376c 在 24 小时和 72 小时被新生儿 HIBI 显着改变,其中 4 个中的 3 个表现出多相表达(24 小时与 72 小时差异表达的不同方向)。

 结论


我们对缺氧或 HIBI 后大脑 miRNA 表达亚急性变化的全球评估将推进基于 miRNA 的靶向干预措施的研究。考虑 HIBI 后的多相 miRNA 表达模式以确定个体干预的最佳时机非常重要。

 影响


  • 这项研究首次全面定义了新生儿缺氧缺血性脑损伤 (HIBI) 后最初几个小时内的内源性脑 microRNA 表达变化。


  • Mir-2137、-335、-137 和 -376c 被新生儿 HIBI 显着改变,因此值得进一步研究作为可能的治疗靶点。


  • 所描述的表达谱将支持未来研究的设计,试图为患有 HIBI 的婴儿开发基于 miRNA 的干预措施。


  • 损伤后 24 小时,对侧 HIBI miRNA 表达模式与同侧 HIBI 比对照更相似,表明对侧大脑不是该模型中 miRNA 研究的合适“内部对照”。

更新日期:2021-08-31
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