细胞色素P450（CYP）酶不仅在药物代谢与药代动力学以及毒理学研究中占有重要地位，而且参与多种疾病的调控，在维持人体健康方面起着重要作用。尽管CYP酶非常重要，但目前可用于研究CYP介导药物代谢或预测与CYP相关的生理病理的动物模型仍然很少。尤其构建新颖的Cyp基因敲除和Cyp人源化大鼠模型更是有利于开展药物代谢、药理以及毒理相关的研究。CRISPR核酸酶作为一种新的靶向基因编辑工具，在动物模型构建方面取得了令人欣喜的效果。我们已创新利用CRISPR技术成功构建特定Cyp基因敲除大鼠模型，并对其基因型和代谢功能进行系统验证和评价。基于以上工作基础，本项目拟通过CRISPR技术构建Cyp基因人源化大鼠并开展药物代谢研究。本项目的实施将在国际上率先得到Cyp基因人源化大鼠模型，不仅为药物代谢与药物动力学研究提供了新模型，还促进了CYP酶与药物药效、毒性、临床用药以及疾病相关的分子机制研究。

Cytochrome P450 (CYP) enzyme not only plays an essential role in drug metabolism and pharmacokinetics，as well as toxicology, but also is involved in many kinds of diseases, and then plays an important role in the maintenance of human health. Although the CYP enzyme is very important, few animal models are used to study CYP mediated drug metabolism or predict CYP properties in physiology and pathology. In particular, the construction of novel Cyp gene knockout and Cyp humanized rat model is conducive to the development of drug metabolism, pharmacological and toxicological studies. CRISPR nuclease as a new target gene editing tool has made a great contribution to the construction of animal model. We have successfully used CRISPR technology to construct specific Cyp knockout rat model, and to verify and evaluate its genotype and metabolic function. Based on the above work, this project intends to use CRISPR technology to construct the Cyp gene humanized rat, and will carry out drug metabolism and pharmacokinetics research using this humanized rat model. The implementation of this project will be the first to obtain Cyp gene humanized rat model, which not only provides a new model for drug metabolism and pharmacokinetic studies, but also promotes the study of molecular mechanisms of CYP enzyme in drug efficacy, toxicity, clinical medicine and related diseases.