A Mouse Model of Gaucher Disease

描述(申请人提供)：高谢病的动物模型可能在研究治疗策略和疾病发病机制的一些特征方面具有重要价值。然而，创建这样一个模式的尝试一直没有成功。这种基因敲除的小鼠在出生时被证明是致命的。我们现在已经创建了一个高谢病的小鼠模型，通过创造一个嵌合体小鼠，将来自基因敲除胎儿的肝脏来源的造血干细胞移植到野生型小鼠身上。这些动物的外周血和脾中的葡萄糖脑苷酶活性不足，而肝和脾中的葡萄糖脑苷含量增加。此外，给动物静脉注射葡萄糖脑苷/白蛋白后，动物体内的葡萄糖脑苷水平进一步增加。我们建议通过研究葡萄糖脑苷蓄积的自然历史来进一步开发这一模型，并试图以更方便、可能更生理学的方式加载这些动物。这种负荷技术可能包括腹腔注射糖脑苷，或通过注射G-CSF或苯肼来增加血细胞的周转。此外，还将探索一种比高效液相色谱法测定葡萄糖脑苷更简便的“读数”方法。特别是，电子显微镜和光学显微镜将被用来试图证明嵌合体小鼠中高雪氏细胞的发育。

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.