论文总字数：17873字

摘 要

斑马鱼（zebrafish，Danio rerio），是一种常用的模式动物。研究表明凭借其自身的特性可以弥补体外细胞实验和体内动物实验的不足。斑马鱼基因与人类基因具有大约87%的同源性，其信号传导通路、生理结构与功能等方面均与哺乳动物十分相似；而且，作为一种整体动物，斑马鱼实验可以十分准确的反映待测药物在体内的吸收、分布、代谢及排泄的动态生理过程。与传统的小鼠体内模型相比，斑马鱼饲养成本低，、繁殖周期短、胚胎透明易于观察、可以实现高通量筛选，因而日益广泛地被用于评估药物的毒性和安全性。

藤黄（gamboge）为藤黄科植物藤黄树分泌的干燥树脂。其中藤黄酸是藤黄的主要活性成分，其具有较强的抗肿瘤活性，能够抑制多种肿瘤细胞。作为一种新型化疗药物，由于治疗肿瘤疗效显著，毒副作用小，藤黄酸在2004年获国家药品监督管理局（SFDA）批准进行临床研究（临床批件号：2004L000333）。I期临床试验结果显示藤黄酸的剂量依赖性毒性主要体现为肝毒性以及肾毒性；IIa期临床试验显示其不良反应程度为I°-II°级。我们前期的实验已经发现藤黄酸可以导致与沙利度胺相似的斑马鱼胚胎的致畸性表型，即胸鳍缺失，产生这种特异性毒性的机理还有待进一步研究。

关键词：斑马鱼 藤黄酸 胸鳍发育 致畸毒性

Study of zebrafish model based on Teratogenicity of gambogic acid

Abstract

Zebrafish (zebrafish, Danio rerio), a commonly used animal model. Vitro experiments and in vivo animal experiments compared to the zebrafish, there are some advantages. Zebrafish and human homology as high as 87%, are highly similar in mammalian signaling pathways, physiological structure and function, at the same time, as a whole animal, the zebrafish experiments can be accurately reflected in the body of the test drug absorption, distribution, metabolism and excretion of dynamic physiological processes, increasingly widely used to assess drug toxicity and safety. compared to the traditional small mouse model in vivo Zebrafish model has some advantageous，such as transparent embryos,low cost, short cycle,can achieve high throughput screening.

Garcinia (gamboge) is Garcinia plant vine Hwang secretion of dry resin. Wherein Garcinia Garcinia acid is the main active ingredient, which has strong anti-tumor activity, can inhibit a variety of tumor cells. As a new chemotherapy drug treatment for solid tumors due to the significant toxic side effects, GA by the State Drug Administration (SFDA) approval to conduct clinical studies (clinical approval document number: 2004L000333) in 2004. Phase I clinical trial results show a dose-dependent toxicity GA mainly reflected hepatotoxicity and nephrotoxicity; IIa clinical trials have shown that adverse reactions for the I ° -II ° degree level. Our previous experiments have found that GA may lead to similar thalidomide teratogenicity zebrafish embryos phenotype, namely lack of pectoral fins, which produce specific toxicity mechanism remains to be further studied.

Key Words: Zebrafish Gambogic acid Pectoral development Teratogenicity

目录

摘要 Ⅰ

Abstract Ⅱ

第一章 文献综述 1

1.1斑马鱼模型在生命科学研究中的应用 1

1.1.1 斑马鱼的简介 2

1.1.2 斑马鱼对化合物（药物）毒性与安全性的评价 2

1.2药物简介 5

1.2.1藤黄酸的理化性质 5

1.2.2 藤黄酸的效用 5

1.2.3 藤黄酸的药动学及动物毒理试验 5

第二章 利用斑马鱼模型评价藤黄酸的致畸毒性 8

2.1 引言 8

2.2 实验材料和方法 8

2.2.1 藤黄酸 8

2.2.2 斑马鱼的饲养 8

2.2.3 主要试剂和耗材 8

2.2.4 主要仪器 9

2.2.5 实验方法 10

2.3 实验结果与讨论 14

2.3.1 藤黄酸急性毒性和致畸毒性结果 14

2.3.2 藤黄酸作用的重要时间段 15

2.3.3 qRT-PCR实验结果 16

2.3.4 结论 17

2.3.5 展望 17

参考文献 18

致谢 20

第一章 文献综述

1.1 斑马鱼模型的应用

1.1.1 斑马鱼模型的简介

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