A Mouse Model of Gaucher Disease

描述（由申请人提供）：戈谢病的动物模型在研究治疗策略和疾病发病机制的某些特征方面可能具有重要价值。然而，建立这种模式的尝试并不成功。基因敲除小鼠在出生时就被证明是致命的。我们现在已经建立了一个戈谢病的小鼠模型，通过创建一个嵌合小鼠，移植野生型小鼠与肝来源的造血干细胞从敲除胎儿。这些动物的外周血和脾脏缺乏葡糖脑苷脂酶活性，肝脏和脾脏中葡糖脑苷脂的量增加。此外，用静脉内给予的葡糖脑苷脂/白蛋白静脉内负荷动物进一步增加葡糖脑苷脂水平。我们建议通过研究葡萄糖脑苷脂积累的自然历史，并试图以更方便和可能更生理的方式加载这些动物，进一步利用这种模型。这种负荷技术可能包括腹膜内注射葡糖脑苷脂或通过给予G-CSF或苯肼增加血细胞周转。一个“读出”，这是更容易比化学测定葡糖脑苷脂的HPLC也将探讨。特别地，将使用电子显微镜和光学显微镜来尝试证明嵌合小鼠中戈谢细胞的发育。

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.