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肝脏人源化

Inducible liver injury-NCG

品系名称:Inducible liver injury-NCG

品系类型:Knock-in

品系编号:T004968

品系背景:NOD/ShiLtJGpt

肝脏是机体进行药物解毒和代谢的最主要的器官,而肝脏人源化小鼠的肝细胞可表达人特异性代谢酶,在药物临床前代谢研究中,更真实的反映药物在人体内的代谢途径,提高药物临床前PK/PD准确性,降低了药物进行人体实验的安全风险。

集萃药康在重度免疫缺陷NCG背景鼠上,制作了可诱导性肝损伤小鼠模型Inducible liver injury-NCG。正常喂养时它不会出现肝损伤,给予药物诱导后才会出现肝损伤,这时可接受人肝细胞的植入。将人原代肝细胞移植到肝损伤小鼠模型体内,构建出肝脏人源化小鼠模型hHeps-NCG

 

hHeps-NCG小鼠在接受人肝细胞移植3周后,即可在血清中检测到人白蛋白(hALB)的表达,9周后人源肝脏重建率可达70%。在人源化小鼠的肝脏可检测到人肝特异性代谢酶的表达。

hHeps NCG小鼠可用于药物代谢研究及病毒性肝炎,尤其是HBV相关研究,为肝脏疾病的病理研究、疫苗和新药研发以及人肝细胞代谢功能的体内研究提供可靠的研究工具。

验证数据

1.        Inducible liver injury-NCG小鼠可出现预期的肝损伤

 

1 Inducible liver injury-NCG小鼠诱导肝损伤后的血生化及肝脏病理检测。

结果显示:正常条件下,Inducible liver injury-NCG小鼠肝脏未出现损伤,给予诱导药物后可产生肝脏损伤。

2.        hHeps-NCG小鼠模型特点

2.1 hHeps-NCG可以实现60%的重建率,外周血中的人白蛋白可达数毫克/毫升的水平。

2 hHeps-NCG小鼠移植人肝细胞后的白蛋白表达检测

hHeps-NCG小鼠接受人肝细胞移植3w后即可在血清中检测到人白蛋白的表达,且白蛋白水平随周龄增加而升高。在移植肝细胞后9w,人白蛋白水平可达到5 mg/mL(图A)。在肝脏组织中,可检测到人白蛋白(hALB)及CK8/18蛋白的表达(图B)。不同重建率的小鼠肝组织切片,棕褐色信号越多,重建率越高(图C)。

2.2 hHeps-NCG小鼠肝脏中可表达人特异性代谢酶

 

3 hHeps-NCG小鼠肝脏人特性代谢酶基因检测。

结果显示:hHeps-NCG小鼠肝脏可表达人肝特异性代谢酶。

 

 

参考文献

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