Baburamani Ana A, Sobotka Kristina S, Vontell Regina, Mallard Carina, Supramaniam Veena G, Thornton Claire, Hagberg Henrik
Perinatal Brain Injury Group, Centre for the Developing Brain, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St. Thomas' Hospital, London, United Kingdom.
Perinatal Center, Institute of Neuroscience and Physiology, Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden.
Oncotarget. 2017 Feb 14;8(7):12081-12092. doi: 10.18632/oncotarget.14518.
Hypoxia-ischemia (HI) can result in permanent life-long injuries such as motor and cognitive deficits. In response to cellular stressors such as hypoxia, tumor suppressor protein p53 is activated, potently initiating apoptosis and promoting Bax-dependent mitochondrial outer membrane permeabilization. The aim of this study was to investigate the effect of Trp53 genetic inhibition on injury development in the immature brain following HI. HI (50 min or 60 min) was induced at postnatal day 9 (PND9) in Trp53 heterozygote (het) and wild type (WT) mice. Utilizing Cre-LoxP technology, CaMK2α-Cre mice were bred with Trp53-Lox mice, resulting in knockdown of Trp53 in CaMK2α neurons. HI was induced at PND12 (50 min) and PND28 (40 min). Extent of brain injury was assessed 7 days following HI. Following 50 min HI at PND9, Trp53 het mice showed protection in the posterior hippocampus and thalamus. No difference was seen between WT or Trp53 het mice following a severe, 60 min HI. Cre-Lox mice that were subjected to HI at PND12 showed no difference in injury, however we determined that neuronal specific CaMK2α-Cre recombinase activity was strongly expressed by PND28. Concomitantly, Trp53 was reduced at 6 weeks of age in KO-Lox Trp53 mice. Cre-Lox mice subjected to HI at PND28 showed no significant difference in brain injury. These data suggest that p53 has a limited contribution to the development of injury in the immature/juvenile brain following HI. Further studies are required to determine the effect of p53 on downstream targets.
缺氧缺血（HI）可导致永久性的终身损伤，如运动和认知缺陷。作为对缺氧等细胞应激源的反应，肿瘤抑制蛋白p53被激活，有力地启动细胞凋亡并促进依赖于Bax的线粒体外膜通透性改变。本研究的目的是探讨Trp53基因抑制对未成熟脑HI后损伤发展的影响。在出生后第9天（PND9）对Trp53杂合子（het）和野生型（WT）小鼠诱导HI（50分钟或60分钟）。利用Cre-LoxP技术，将CaMK2α-Cre小鼠与Trp53-Lox小鼠杂交，导致CaMK2α神经元中Trp53基因敲低。在PND12（50分钟）和PND28（40分钟）诱导HI。HI后7天评估脑损伤程度。在PND9进行50分钟HI后，Trp53 het小鼠在后海马和丘脑显示出保护作用。在严重的60分钟HI后，WT或Trp53 het小鼠之间未见差异。在PND12接受HI的Cre-Lox小鼠在损伤方面无差异，然而我们确定神经元特异性CaMK2α-Cre重组酶活性在PND28时强烈表达。同时，KO-Lox Trp53小鼠在6周龄时Trp53减少。在PND28接受HI的Cre-Lox小鼠在脑损伤方面无显著差异。这些数据表明，p53对未成熟/幼年脑HI后损伤发展的作用有限。需要进一步研究来确定p53对下游靶点的影响。
