Evaluation of disease model traits in cultured cells derived from carnitine deficient JVS mice

隐性突变基因JVS纯合的JVS小鼠表现出多种病理综合征，如脂肪肝、高血氧症、心肌肥厚、雄性生育能力下降、异常；尿素循环酶相关基因的表达。在这个项目中，我们试图评估这些综合征的基础，在原代培养细胞或建立细胞系从JVS胚胎。虽然我们有以下新发现，但我们认为，很难从JVS胚胎或新生幼鼠的培养细胞中预测JVS小鼠的各种特异性综合征。似乎需要进一步完善的细胞或组织培养方法来评估体内综合征。在增大的心肌中，一些肌细胞细胞核增大，线粒体增多。如切片肾所见，原代培养的胚胎细胞和成纤维细胞对游离肉碱的吸收活性较低。体外对肉毒碱的摄取取决于突变基因jvs的基因剂量。虽然JVS的精子发生在形态学上是正常的，但似乎附睾的成熟过程受到了损害，导致JVS雄性小鼠部分不育。即使在最一般的实验动物室条件下，JVS的冷致产热也会变迟钝，而添加左旋肉碱可以部分改善这种迟钝的产热。^ 3h标记肉毒碱（口服或静脉注射）后，游离肉毒碱的体积分布明显降低，除脑外各器官游离肉毒碱浓度相对于血浆浓度也较正常对照组低，JVS口服肉毒碱后游离肉毒碱的生物利用度约为正常对照组的50%。

JVS mice which are homozygous for recessive mutant gene jvs exhibit various pathological syndromes, such as fatty liver, htperanmonemia, cardiac hypertrophy, reduced fertility in males, and abnormal ; expression of genes related to urea cycle enzymes. In this project we attempt to assess the basis of these syndromes in primary cultured cells or establisjed cell lined from the JVS embryos.Although we have newly made following findings, it is concluded that various specific syndromes in the JVS mice are difficult to predict from cultured cells from the JVS embryos or new born pups. It seems that further elaborated methods for cell or tissue culture are neede to assess the syndrome in vivo.1. In enlarged heart muscle some muscle cells have an enlarged nucleus and the increased mitochondoria.2. As seen in sliced kidney, primary cultured embryonic cells and established fibloblastic cells are less active in uptake of free carnitine. The carnitine uptake in in vitro is depend on gene dose of mutant gene jvs.3. Although spermatogenesis in JVS is apparently morphologically normal, it seems that the maturation process in epydidimus is impaired, and it resulted in partial sterility in JVS male mice.4. Cold-Induced thermogenesis in JVS was blunted even in the most general condition of laboratory animal room and that the blunted thermogenesis was partially improved with L-carnitine supplement.5. Volume distribution of free carnitine after ^3H-labeled carnitine administration (oral or iv) was significantly reduced and the concentration of free carnitin various organs except brain relative to that of plasma is also lower compared normal controls and bioavailability of free carnitine after oral administration of carnitine in JVS was about 50% of normal control value.