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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Modeling CTLA4-linked autoimmunity with RNA interference in mice
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Modeling CTLA4-linked autoimmunity with RNA interference in mice

机译：用RNA干扰在小鼠中模拟CTLA4连锁的自身免疫

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摘要

The CTLA4 gene is important for T lymphocyte-mediated immunoregulation and has been associated with several autoimmune diseases, in particular, type 1 diabetes. To model the impact of natural genetic variants of CTLA4, we constructed RNA interference (RNAi) "knockdown" mice through lentiviral transgenesis. Variegation of expression was observed in founders but proved surmountable because it reflected parental imprinting, with derepression by transmission from male lentigenics. Unlike the indiscriminate multiorgan autoimmune phenotype of the corresponding knockout mice, Ctla4 knockdown animals had a disease primarily focused on the pancreas, with rapid progression to diabetes. As with the human disease, the knockdown phenotype was tempered by genetic-modifier loci. RNAi should be more pertinent than gene ablation in modeling disease pathogenesis linked to a gene-dosage variation.
机译：CTLA4基因对于T淋巴细胞介导的免疫调节很重要，并且已与几种自身免疫性疾病（尤其是1型糖尿病）相关。为了模拟CTLA4的自然遗传变异的影响，我们通过慢病毒转基因构建了RNA干扰（RNAi）“敲低”小鼠。在创始人中发现了表达变异，但由于它反映了父母的印记，并通过从男性慢生基因传播而引起的抑制而被证明是可克服的。与相应的基因敲除小鼠的多器官自身免疫表型不同，Ctla4基因敲除动物的疾病主要集中在胰腺，并迅速发展为糖尿病。与人类疾病一样，基因修饰基因座也能降低基因敲除的表型。在模拟与基因剂量变异有关的疾病发病机理时，RNAi应该比基因消融更为相关。

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