Maria D Gallardo, Mauricio Girard, Enrique L Portiansky, Rodolfo G Goya
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引用次数: 0
摘要
在中年(MA)雌性大鼠中,我们已经证明下丘脑内胰岛素样生长因子- i (IGF-I)基因治疗延长了动物的正常周期超过10个月(MA大鼠停止排卵的年龄)。在这里,我们对年轻雌性大鼠的下丘脑进行了长期的OSKM基因治疗。主要目标是延长治疗动物的生育能力。我们构建了一个包含GFP基因和4个Yamanaka基因的腺载体。只携带GFP或DsRed基因的腺载体作为对照。在12个月大时,雌性大鼠接受下丘脑内注射我们的OSKM载体(处理大鼠);12只对照大鼠接受表达标记基因的载体(对照大鼠)。在9.3月龄时,对照组和实验组大鼠与年轻雄性交配。一组12只年轻的雌性老鼠也进行了交配。幼鼠、MA对照组和MA处理鼠的妊娠率分别为83%、8.3和25%。MA OSKM大鼠断奶时幼仔体重(BW)显著高于MA对照组。在绝经期(10个月),OSKM治疗的雌性仍有规律的发情周期。本研究结果的特殊意义在于,首次表明下丘脑的长期OSKM基因治疗能够扩展下丘脑-垂体-卵巢轴这样一个复杂系统的功能。
Oct4, Sox2, Klf4, c-My (OSKM) gene therapy in the hypothalamus prolongs fertility and ovulation in female rats.
In middle-aged (MA) female rats, we have demonstrated that intrahypothalamic gene therapy for insulin-like growth factor-I (IGF-I) extends the regular cyclicity of the animals beyond 10 months (the age at which MA rats stop ovulating). Here, we implemented long-term OSKM gene therapy in the hypothalamus of young female rats. The main goal was to extend fertility in the treated animals. We constructed an adenovector that harbors the GFP gene as well as 4 Yamanaka genes. An adenovector that only carries the gene for GFP or DsRed was used as control. At 4 months of age 12 female rats received an intrahypothalamic injection of our OSKM vector (treated rats); 12 control rats received a vector expressing a marker gene (control rats). At 9.3 months of age control and treated rats were mated with young males. A group of 12 young intact female rats was also mated. The rate of pregnancy recorded was 83%, 8.3 and 25% for young, MA control and MA treated animals, respectively. Pup body weight (BW) at weaning was significantly higher in the MA OSKM rats than in MA controls. At the age of estropause (10 months), OSKM treated females still showed regular estrous cycles. The particular significance of the present results is that, for the first time, it is shown that long-term OSKM gene therapy in the hypothalamus is able to extend the functionality of such a complex system as the hypothalamo-pituitary-ovarian axis.