A Mouse Model of Gaucher Disease

描述（申请人提供）：戈谢病的动物模型对研究该病的治疗策略和发病机制的一些特征具有重要价值。然而，创建这样一个模型的尝试一直没有成功。被敲除的老鼠在出生时就被证明是致命的。我们现在通过创造嵌合小鼠，移植野生型小鼠与来自基因敲除胎儿的肝脏来源的造血干细胞，创造了戈谢病的小鼠模型。这些动物的外周血和脾脏缺乏葡萄糖脑苷酶活性，肝脏和脾脏中葡萄糖脑苷的含量增加。此外，静脉注射糖脑苷/白蛋白的动物进一步增加了糖脑苷水平。我们建议通过研究糖脑苷积累的自然历史，并尝试以更方便和可能更生理的方式加载这些动物，进一步利用这一模型。这种装载技术可能包括腹腔注射葡萄糖脑苷或通过给药G-CSF或苯肼来增加血细胞周转。我们还将探讨一种比高效液相色谱法测定糖脑苷更简便的“读出法”。特别是，电子显微镜和光学显微镜将被用来试图证明戈谢细胞在嵌合小鼠中的发育。

DESCRIPTION (provided by applicant): An animal model of Gaucher disease could be of great value in studying treatment strategies and some features of the pathogenesis of the disease. However, attempts to create such a model have been unsuccessful. The knockout mouse proved to be lethal at about the time of birth. We have now created a murine model of Gaucher disease by creating a chimeric mouse, transplanting wildtype mice with liver-derived hematopoietic stem cells from knockout fetuses. The peripheral blood and spleen from these animals is deficient in glucocerebrosidase activity and the amount of glucocerebroside in the liver and spleen is increased. Moreover, intravenous loading of the animals with glucocerebroside/albumin given intravenously increases the glucocerebroside levels further. We propose to further exploit this model by studying the natural history of glucocerebroside accumulation and by attempting to load these animals in a more convenient and possibly more physiologic manner. Such loading techniques might consist of intraperitoneal injection of glucocerebroside or the increase of blood cell turnover by the administration of G-CSF or phenylhydrazine. A "readout" that is more facile than chemical determination of glucocerebroside by HPLC will also be explored. In particular, electron microscopy and light microscopy will be used to attempt to demonstrate the development of Gaucher cells in the chimeric mice.