本文選題：黃嘌呤氧化還原酶抑制劑篩選模型 + 急性高尿酸血癥小鼠模型　； 參考：《北京協(xié)和醫(yī)學院》2017年碩士論文

【摘要】：高尿酸血癥(hyperuricemia,HUA)是一種代謝性疾病,由嘌呤代謝紊亂所致,不但是痛風的直接致病因素,而且還與代謝綜合征、慢性腎病、心血管疾病密切聯(lián)系。臨床上在對上述疾病的防治中,越來越關注對血尿酸的控制。高尿酸血癥患者人群龐大,但用于治療痛風和控制血尿酸的藥物還相對缺乏,傳統(tǒng)的降尿酸藥物已不能滿足臨床實際需要,藥物研發(fā)需求迫切。現(xiàn)有的篩選方法中,體外黃嘌呤氧化還原酶(Xanthine oxidoreductase,XOD)來源多樣,其抑制劑篩選容易出現(xiàn)假陰性和假陽性結(jié)果;整體水平的模型動物種屬多樣,存在血尿酸維持不穩(wěn)定等問題,限制了抗高尿酸血癥藥物的研發(fā)。本研究首先利用牛奶來源黃嘌呤氧化還原酶XOD1(PDBID:3AMZ),建立了 XOD抑制劑體外篩選模型;并應用該模型篩選樣品1566個,發(fā)現(xiàn)活性較好的樣品20個。其次,利用氧嗪酸鉀(Potassium Oxonate,OXO)合并次黃嘌呤(Hypoxanthine,HA)單次刺激形成血尿酸一過性升高的急性高尿酸血癥小鼠模型,探討了其XOD活性、肝腎功能等一般特征;并應用該模型評價了9個樣品的抗急性高尿酸血癥的藥效。最后,利用OXO多次給藥形成慢性高尿酸血癥小鼠模型,探討了其XOD活性、肝腎功能等一般特征;并應用該模型評價了 4個樣品治療小鼠慢性高尿酸血癥的藥效。綜上,本研究建立了基于靶點XOD的抗高尿酸血癥藥物體外和體內(nèi)藥物篩選實驗體系,并應用該實驗體系開展藥物篩選和藥效評價,為抗高尿酸血癥藥物研發(fā)奠定了實驗基礎。
[Abstract]:Hyperuricemia (HUAA) is a metabolic disease caused by metabolic disorder of purine, which is not only a direct pathogenic factor of gout, but also closely related to metabolic syndrome, chronic nephropathy and cardiovascular disease. More and more attention has been paid to the control of serum uric acid in the prevention and treatment of these diseases. There is a large population of patients with hyperuricemia, but the drugs used to treat gout and control uric acid are relatively scarce. The traditional anti-uric acid drugs can not meet the actual clinical needs, and the need for drug development is urgent. Among the existing screening methods, Xanthine oxidoreductase XODs in vitro come from a variety of sources, and the screening of Xanthine oxidoreductase XODs is prone to false negative and false positive results. It limits the development of anti-hyperuricemia drugs. In this study, an in vitro screening model of XOD inhibitor was established by using xanthine redox enzyme XOD1: PDBID: 3AMZN, and 1566 samples were screened by the model, and 20 samples with good activity were found. Secondly, an acute hyperuricemia mouse model was established by single stimulation of Potassium OxonateOXO combined with Hypoxanthine Hypoxanthine (HAH), and its XOD activity, liver and kidney function were studied. The model was used to evaluate the antihyperuricemia effect of 9 samples. Finally, the mice model of chronic hyperuricemia was established by using OXO for many times, and the general characteristics of XOD activity, liver and kidney function were discussed, and the pharmacodynamics of 4 samples in treating chronic hyperuricemia in mice was evaluated. In conclusion, a drug screening system for anti-hyperuricemia drugs in vitro and in vivo was established based on the target XOD, and the experimental system was used to screen drugs and evaluate their efficacy, which laid an experimental foundation for the research and development of anti-hyperuricemia drugs.
【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R589.7

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本文編號：2011247