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首页> 外文期刊>Molecular and Cellular Biology >Targeted Deletion of Both Thymidine Phosphorylase and Uridine Phosphorylase and Consequent Disorders in Mice
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Targeted Deletion of Both Thymidine Phosphorylase and Uridine Phosphorylase and Consequent Disorders in Mice

机译：小鼠胸苷磷酸化酶和尿苷磷酸化酶的靶向删除及随之而来的疾病

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Thymidine phosphorylase (TP) regulates intracellular and plasma thymidine levels. TP deficiency is hypothesized to (i) increase levels of thymidine in plasma, (ii) lead to mitochondrial DNA alterations, and (iii) cause mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). In order to elucidate the physiological roles of TP, we generated mice deficient in the TP gene. Although TP activity in the liver was inhibited in these mice, it was fully maintained in the small intestine. Murine uridine phosphorylase (UP), unlike human UP, cleaves thymidine, as well as uridine. We therefore generated TP-UP double-knockout (TP?/? UP?/?) mice. TP activities were inhibited in TP?/? UP?/? mice, and the level of thymidine in the plasma of TP?/? UP?/? mice was higher than for TP?/? mice. Unexpectedly, we could not observe alterations of mitochondrial DNA or pathological changes in the muscles of the TP?/? UP?/? mice, even when these mice were fed thymidine for 7 months. However, we did find hyperintense lesions on magnetic resonance T2 maps in the brain and axonal edema by electron microscopic study of the brain in TP?/? UP?/? mice. These findings suggested that the inhibition of TP activity caused the elevation of pyrimidine levels in plasma and consequent axonal swelling in the brains of mice. Since lesions in the brain do not appear to be due to mitochondrial alterations and pathological changes in the muscle were not found, this model will provide further insights into the causes of MNGIE.
机译：胸苷磷酸化酶（TP）调节细胞内和血浆胸苷水平。 TP缺乏被假定为（i）血浆中胸腺嘧啶核苷水平升高，（ii）导致线粒体DNA改变，以及（iii）引起线粒体神经胃肠道脑病（MNGIE）。为了阐明TP的生理作用，我们生成了 TP 基因缺陷的小鼠。尽管在这些小鼠中肝脏中的TP活性受到抑制，但在小肠中完全保持了TP活性。鼠尿苷磷酸化酶（UP）与人UP不同，它裂解胸苷和尿苷。因此，我们生成了TP-UP双敲除（TP ？/？ UP ？/？）小鼠。 TP ？/？ UP ？/？小鼠的TP活性受到抑制，TP ？/？ UP血浆中的胸苷水平受到抑制？/？小鼠高于TP ？/？小鼠。出乎意料的是，即使给这些小鼠喂了胸腺嘧啶核苷，我们也无法观察到TP ？/？ UP ？/？小鼠的线粒体DNA改变或肌肉的病理变化。 7个月。但是，通过在TP ？/？ UP ？中对大脑进行的电子显微镜研究，我们确实在大脑的磁共振T 2 图和轴突水肿中发现了高强度病变。 /？小鼠。这些发现表明，TP活性的抑制引起血浆中嘧啶水平的升高，并因此导致小鼠脑中的轴突肿胀。由于大脑中的损伤似乎不是由于线粒体的改变而引起的，而且未发现肌肉的病理变化，因此该模型将为了解MNGIE的原因提供进一步的见解。

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