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Sci Signal:上海中医药大学陈瑜研究组等发表信号转导新文章

摘要 : 2016年7月26日,国际顶尖学术期刊《Science》旗下《Science Signaling》杂志上在线发表了上海中医药大学陈瑜教授和凯斯西储大学Krzysztof Palczewski教授合作的一篇研究论文,研究证实协同作用的G蛋白偶联受体激动剂与拮抗剂可以阻止光感受器细胞退化。

 2016年7月26日,国际顶尖学术期刊《Science》旗下《Science Signaling》杂志上在线发表了上海中医药大学陈瑜教授和凯斯西储大学Krzysztof Palczewski教授合作的一篇研究论文,研究证实协同作用的G蛋白偶联受体激动剂与拮抗剂可以阻止光感受器细胞退化。

文章中报道研究人员采用了一种系统药理学方法,利用光诱导视网膜退化小鼠模型来鉴别出潜在联合疗法。研究人员证实联合使用对不同的GPCRs起作用的药物,显示出协同活性保护了视网膜免于光诱导的退化,甚至是在低剂量给予每种药物时。

在功能分析中,研究人员证实这些药物是通过激活多巴胺受体D2R和D4R刺激Gi/o信号,以及通过拮抗D1R和α1A-肾上腺素能受体ADRA1A抑制Gs和Gq信号来发挥了联合效应。此外,转录组分析证实相比给予较高剂量的单药治疗,这样的联合GPCR靶向疗法保持的视网膜基因表达模式与正常视网膜更相似。

这项研究由此支持了采用一种系统药理学方法来鉴别视网膜病变的治疗方法,并且这一方法还可以扩展应用于其他的复杂疾病。

原文链接:

Synergistically acting agonists and antagonists of G protein–coupled receptors prevent photoreceptor cell degeneration

原文摘要:

Photoreceptor cell degeneration leads to visual impairment and blindness in several types of retinal disease. However, the discovery of safe and effective therapeutic strategies conferring photoreceptor cell protection remains challenging. Targeting distinct cellular pathways with low doses of different drugs that produce a functionally synergistic effect could provide a strategy for preventing or treating retinal dystrophies. We took a systems pharmacology approach to identify potential combination therapies using a mouse model of light-induced retinal degeneration. We showed that a combination of U.S. Food and Drug Administration–approved drugs that act on different G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors (GPCRs) exhibited synergistic activity that protected retinas from light-induced degeneration even when each drug was administered at a low dose. In functional assays, the combined effects of these drugs were stimulation of Gi/o signaling by activating the dopamine receptors D2R and D4R, as well as inhibition of Gs and Gq signaling by antagonizing D1R and the α1A-adrenergic receptor ADRA1A, respectively. Moreover, transcriptome analyses demonstrated that such combined GPCR-targeted treatments preserved patterns of retinal gene expression that were more similar to those of the normal retina than did higher-dose monotherapy. Our study thus supports a systems pharmacology approach to identify treatments for retinopathies, an approach that could extend to other complex disorders.

来源: Science Signaling 浏览次数:0

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