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转录因子靶基因网络控制利什曼病合成回路的逻辑抽象分析。

Transcription Factor Target Gene Network governs the Logical Abstraction Analysis of the Synthetic Circuit in Leishmaniasis.

机构信息

National Centre for Cell Science, NCCS Complex, Ganeshkhind, SP Pune University Campus, Pune, 411007, India.

出版信息

Sci Rep. 2018 Feb 22;8(1):3464. doi: 10.1038/s41598-018-21840-w.

Abstract

With the advent of synthetic biology in medicine many synthetic or engineered proteins have made their way to therapeutics and diagnostics. In this paper, the downstream gene network of CD14-TNF-EGFR pathway in leishmaniasis, a tropical disease, is reconstructed. Network analysis showed that NFkB links the signaling and gene network, used as a point of intervention through a synthetic circuit embedded within the negative autoregulatory feedback loop. A chimeric protein kinase C (PKC) is incorporated in the synthetic circuit, under the transcriptional regulation of Lac repressor and IPTG, as an inducer. The chimeric PKC_ζα via IκKb phosphorylation activates NFκB, and modulates the gene expression from an anti-inflammatory to a pro-inflammatory phenotype in in vitro L. major infected macrophage model. This is the first ever report of a synthetic device construction in leishmania.

摘要

随着医学中合成生物学的出现,许多合成或工程蛋白已经应用于治疗和诊断。在本文中,我们重建了热带疾病利什曼病中 CD14-TNF-EGFR 途径的下游基因网络。网络分析表明,NFkB 连接信号和基因网络,可作为通过嵌入负反馈回路中的合成电路进行干预的切入点。在 Lac 阻遏物和 IPTG 的转录调控下,将嵌合蛋白激酶 C(PKC)整合到合成电路中作为诱导剂。嵌合 PKC_ζα 通过 IκKb 磷酸化激活 NFκB,并调节体外 L. major 感染的巨噬细胞模型中从抗炎到促炎表型的基因表达。这是在利什曼原虫中构建合成装置的首例报道。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ad1e/5823942/ccdf8ffe6b7e/41598_2018_21840_Fig1_HTML.jpg

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