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首页> 外文期刊>Nucleic Acid Therapeutics >Hybrid Mouse Diversity Panel Identifies Genetic Architecture Associated with the Acute Antisense Oligonucleotide-Mediated Inflammatory Response to a 2 '-O-Methoxyethyl Antisense Oligonucleotide
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Hybrid Mouse Diversity Panel Identifies Genetic Architecture Associated with the Acute Antisense Oligonucleotide-Mediated Inflammatory Response to a 2 '-O-Methoxyethyl Antisense Oligonucleotide

机译：混合鼠标分集面板识别与急性反义寡核苷酸介导的炎症反应与2'-O-甲氧基乙基反义寡核苷酸相关的遗传建筑

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Although antisense oligonucleotides (ASOs) are well tolerated preclinically and in the clinic, some sequences of ASOs can trigger an inflammatory response leading to B cell and macrophage activation in rodents. This prompted our investigation into the contribution of genetic architecture to the ASO-mediated inflammatory response. Genome-wide association (GWA) and transcriptomic analysis in a hybrid mouse diversity panel (HMDP) were used to identify and validate novel genes involved in the acute and delayed inflammatory response to a single 75 mg/kg dose of an inflammatory 2 '-O-methoxyethyl (2 ' MOE) modified ASO. The acute response was measured 6 h after ASO administration, via evaluation for increased plasma production of interleukin 6 (IL6), IL10, monocyte chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein-1 beta (MIP-1 beta). Delayed inflammation was evaluated by spleen weight increases after 96 h. We identified single nucleotide polymorphisms (SNPs) on chromosomes 16 and 17 associated with plasma MIP-1 beta, IL6, and MCP-1 levels, and one on chromosome 8 associated with increases in spleen weight. Systems genetic analysis utilizing transcriptomic data from HMDP strain macrophages determined that the acute inflammatory SNPs were expression quantitative trait locis (eQTLs) for CCAAT/enhancer-binding protein beta (Cebpb) and salt inducible kinase 1 (Sik1). The delayed inflammatory SNP was an eQTL for Rho guanine nucleotide exchange factor 10 (Arhgef10). In vitro assays in mouse primary cells and human cell lines have confirmed the HMDP finding that lower Sik1 expression increases the acute inflammatory response. Our results demonstrate the utility of using mouse GWA study (GWAS) and the HMDP for detecting genes modulating the inflammatory response to pro-inflammatory ASOs in a pharmacological setting.
机译：虽然反义寡核苷酸（ASOS）尿液尿寡核苷酸（ASOS）在临床上并且在临床中，但是一些ASO的序列可以引发导致B细胞和啮齿动物巨噬细胞活化的炎症反应。这促使我们调查遗传架构对肌介质炎症反应的贡献。杂交小鼠分集面板（HMDP）中的基因组关联（GWA）和转录组分析用于鉴定和验证参与急性和延迟炎症反应的新基因，对炎性2'-O的单一75mg / kg剂量 - 甲氧基乙基（2'Moe）改性ASO。通过评估在ASO给药后6小时测量急性反应，所述运动蛋白6（IL6），IL10，单核细胞化学蛋白1（MCP-1）和巨噬细胞炎症蛋白-1β（MIP-1β）的血浆产生增加。通过脾脏重量评估延迟炎症在96小时后增加。我们在染色体16和17上鉴定了与血浆MIP-1β，IL6和MCP-1水平相关的单核苷酸多态性（SNP），以及与脾脏重量增加相关的染色体8上。系统遗传分析利用来自HMDP菌株巨噬细胞的转录组族数据的遗传分析确定了急性炎症SNP是CCAAT /增强子结合蛋白β（CEBPB）和盐诱导激酶1（SIK1）的表达定量性状轨迹（EQTLS）。延迟的炎症SNP是RHO鸟嘌呤核苷酸交换因子10（ARHGEF10）的EQTL。在小鼠初级细胞和人细胞系中的体外测定证实了HMDP发现降低Sik1表达增加了急性炎症反应。我们的结果证明了使用小鼠GWA研究（GWAS）和HMDP检测试验在药理学环境中对促炎症ASOS的炎症反应的基因进行检测的效用。

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