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基于适配体的查加斯病药物研发小鼠模型中疾病生物标志物的检测

Aptamer-based detection of disease biomarkers in mouse models for chagas drug discovery.

作者信息

de Araujo Fernanda Fortes, Nagarkatti Rana, Gupta Charu, Marino Ana Paula, Debrabant Alain

机构信息

Laboratory of Emerging Pathogens, Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland, United States of America.

Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.

出版信息

PLoS Negl Trop Dis. 2015 Jan 8;9(1):e3451. doi: 10.1371/journal.pntd.0003451. eCollection 2015 Jan.

Abstract

Drug discovery initiatives, aimed at Chagas treatment, have been hampered by the lack of standardized drug screening protocols and the absence of simple pre-clinical assays to evaluate treatment efficacy in animal models. In this study, we used a simple Enzyme Linked Aptamer (ELA) assay to detect T. cruzi biomarker in blood and validate murine drug discovery models of Chagas disease. In two mice models, Apt-29 ELA assay demonstrated that biomarker levels were significantly higher in the infected group compared to the control group, and upon Benznidazole treatment, their levels reduced. However, biomarker levels in the infected treated group did not reduce to those seen in the non-infected treated group, with 100% of the mice above the assay cutoff, suggesting that parasitemia was reduced but cure was not achieved. The ELA assay was capable of detecting circulating biomarkers in mice infected with various strains of T. cruzi parasites. Our results showed that the ELA assay could detect residual parasitemia in treated mice by providing an overall picture of the infection in the host. They suggest that the ELA assay can be used in drug discovery applications to assess treatment efficacy in-vivo.

摘要

针对恰加斯病治疗的药物研发工作,因缺乏标准化的药物筛选方案以及缺乏用于评估动物模型治疗效果的简单临床前检测方法而受阻。在本研究中,我们使用了一种简单的酶联适体(ELA)检测法来检测血液中的克氏锥虫生物标志物,并验证恰加斯病的小鼠药物研发模型。在两个小鼠模型中,Apt - 29 ELA检测法表明,与对照组相比,感染组的生物标志物水平显著更高,而在接受苯并硝唑治疗后,其水平降低。然而,感染治疗组的生物标志物水平并未降至未感染治疗组的水平,100%的小鼠高于检测临界值,这表明寄生虫血症有所降低,但未实现治愈。ELA检测法能够检测感染不同克氏锥虫菌株的小鼠体内的循环生物标志物。我们的结果表明,ELA检测法通过提供宿主感染的整体情况,能够检测治疗小鼠体内的残余寄生虫血症。结果表明,ELA检测法可用于药物研发应用中,以评估体内治疗效果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/54c0/4287562/153c3bba835a/pntd.0003451.g001.jpg

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