In vivo RNA interference demonstrates a role for Nramp1 in modifying susceptibility to type 1 diabetes
In vivo RNA interference demonstrates a role for Nramp1 in modifying susceptibility to type 1 diabetes
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DOI：
10.1038/ng1766
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发表时间：
2006-04-01
期刊：
影响因子：
30.8
通讯作者：
Wicker, LS
中科院分区：
文献类型：
--
作者：
Kissler, S;Stern, P;Wicker, LS
1型糖尿病是一种自身免疫性疾病，受多个遗传位点的影响。尽管在非肥胖糖尿病（NOD）小鼠模型中发现了20多个胰岛素依赖性糖尿病（Idd）基因座（1，2），但几乎没有发现致病基因变异（3，4）。在这里，我们表明，RNA干扰（5，6）（RNAi）可用于探测这种疾病模型中的候选基因。Slc 11 a1编码吞噬体离子转运蛋白Nramp 1，其影响对细胞内病原体的抗性并影响抗原呈递（7-9）。该基因是Idd5.2区域中42个基因中最强的候选基因;保护性Idd5.2单倍型中自然发生的突变导致Nramp 1蛋白功能丧失（10）。使用慢病毒转基因（11），我们产生了NOD小鼠，其中Slc 11 a1被RNAi沉默。沉默降低了1型糖尿病的发生率，模拟了保护性Idd 5.2区域。我们的研究结果证明了Slc 11 a1在改变1型糖尿病易感性中的作用，并说明RNAi可用于研究哺乳动物模型生物中的致病基因。
Type 1 diabetes is an autoimmune disease influenced by multiple genetic loci. Although more than 20 insulin-dependent diabetes (Idd) loci have been implicated in the nonobese diabetic (NOD) mouse model(1,2), few causal gene variants have been identified(3,4). Here we show that RNA interference(5,6) (RNAi) can be used to probe candidate genes in this disease model. Slc11a1 encodes a phagosomal ion transporter, Nramp1, that affects resistance to intracellular pathogens and influences antigen presentation(7-9). This gene is the strongest candidate among the 42 genes in the Idd5.2 region; a naturally occurring mutation in the protective Idd5.2 haplotype results in loss of function of the Nramp1 protein(10). Using lentiviral transgenesis(11), we generated NOD mice in which Slc11a1 is silenced by RNAi. Silencing reduced the frequency of type 1 diabetes, mimicking the protective Idd5.2 region. Our results demonstrate a role for Slc11a1 in modifying susceptibility to type 1 diabetes and illustrate that RNAi can be used to study causal genes in a mammalian model organism.