Functional Assessment of Stroke-Induced Regulation of miR-20a-3p and Its Role as a Neuroprotectant.
Functional Assessment of Stroke-Induced Regulation of miR-20a-3p and Its Role as a Neuroprotectant.
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DOI：
10.1007/s12975-021-00945-x
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发表时间：
2022-06
影响因子：
6.9
通讯作者：
Sohrabji, Farida
中科院分区：
文献类型：
--
作者：
Branyan, Taylor E.;Selvamani, Amutha;Park, Min Jung;Korula, Kriti E.;Kosel, Kelby F.;Srinivasan, Rahul;Sohrabji, Farida
MicroRNA作为包括中风在内的许多疾病的潜在治疗方法而受到欢迎。本研究鉴定并表征了miR-17-92簇的特定成员miR-20 a-3 p作为可能的中风治疗剂。一项全面的microRNA筛选显示，miR-20 a-3 p在成年雌性大鼠的星形胶质细胞中显著上调，这些大鼠通常具有更好的中风结局，而在中年女性和成年和中年男性的星形胶质细胞中则显著下调，这些群体通常具有更严重的中风结局。使用原代人星形胶质细胞和神经元的测定显示，miR-20 a-3 p处理改变了两种细胞类型中的线粒体动力学。为了评估是否可以通过提高星形胶质细胞miR-20 a-3 p来改善卒中结局，我们创建了四环素（泰特）诱导的重组腺相关病毒（rAAV）构建体，其中miR-20 a-3 p位于胶质细胞酸性蛋白启动子下游。用强力霉素治疗诱导星形胶质细胞中的miR-20- 3 p表达，降低死亡率并适度改善感觉运动行为。建立了第二个Tet-induced rAAV构建体，其中miR-20 a-3 p位于神经元特异性烯醇化酶（NSE）启动子的下游。这些实验表明，miR-20 a-3 p的神经元表达比星形胶质细胞表达具有更强的神经保护作用，接受miR-20 a-3 p载体的动物显示出减少的梗死和感觉运动改善。静脉内注射，这是一种治疗上容易处理的治疗途径，在大脑中动脉闭塞（MCAo）后4小时用miR-20 a-3 p模拟物显著改善中风结果，包括梗死体积和感觉运动表现。当在MCAo后立即或24小时给予miR-20 a-3 p时，未观察到改善，确定了独特的延迟治疗窗。总的来说，这项研究确定了一种新的神经保护性microRNA，并描述了它可以改善中风结局的几个关键途径。在线版本包含补充材料，可通过10.1007/s12975-021-00945-x获取。
MicroRNAs have gained popularity as a potential treatment for many diseases, including stroke. This study identifies and characterizes a specific member of the miR-17–92 cluster, miR-20a-3p, as a possible stroke therapeutic. A comprehensive microRNA screening showed that miR-20a-3p was significantly upregulated in astrocytes of adult female rats, which typically have better stroke outcomes, while it was profoundly downregulated in astrocytes of middle-aged females and adult and middle-aged males, groups that typically have more severe stroke outcomes. Assays using primary human astrocytes and neurons show that miR-20a-3p treatment alters mitochondrial dynamics in both cell types. To assess whether stroke outcomes could be improved by elevating astrocytic miR-20a-3p, we created a tetracycline (Tet)-induced recombinant adeno-associated virus (rAAV) construct where miR-20a-3p was located downstream a glial fibrillary acidic protein promoter. Treatment with doxycycline induced miR-20-3p expression in astrocytes, reducing mortality and modestly improving sensory motor behavior. A second Tet-induced rAAV construct was created in which miR-20a-3p was located downstream of a neuron-specific enolase (NSE) promoter. These experiments demonstrate that neuronal expression of miR-20a-3p is vastly more neuroprotective than astrocytic expression, with animals receiving the miR-20a-3p vector showing reduced infarction and sensory motor improvement. Intravenous injections, which are a therapeutically tractable treatment route, with miR-20a-3p mimic 4 h after middle cerebral artery occlusion (MCAo) significantly improved stroke outcomes including infarct volume and sensory motor performance. Improvement was not observed when miR-20a-3p was given immediately or 24 h after MCAo, identifying a unique delayed therapeutic window. Overall, this study identifies a novel neuroprotective microRNA and characterizes several key pathways by which it can improve stroke outcomes. The online version contains supplementary material available at 10.1007/s12975-021-00945-x.
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影响因子：
4.2
作者：
Lewis DK;Thomas KT;Selvamani A;Sohrabji F
通讯作者：
Sohrabji F
影响因子：
4.5
作者：
Angel Maciel-Baron, Luis;Lizbeth Morales-Rosales, Sandra;Konigsberg, Mina
通讯作者：
Konigsberg, Mina
DOI：
10.1097/00004647-199611000-00036
发表时间：
1996-11-01
影响因子：
6.3
作者：
Hamann, GF;Okada, Y;delZoppo, GJ
通讯作者：
delZoppo, GJ
影响因子：
6.7
作者：
Ham, P. Benson, III;Raju, Raghavan
通讯作者：
Raju, Raghavan
DOI：
10.1177/0271678x15610786
发表时间：
2016-08
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
Liu da Z;Jickling GC;Ander BP;Hull H;Zhan X;Cox C;Shroff N;Dykstra-Aiello C;Stamova B;Sharp FR
通讯作者：
Sharp FR