Systemic leukocyte-directed siRNA delivery revealing cyclin D1 as an anti-inflammatory target
Systemic leukocyte-directed siRNA delivery revealing cyclin D1 as an anti-inflammatory target
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DOI：
10.1126/science.1149859
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发表时间：
2008-02-01
期刊：
影响因子：
56.9
通讯作者：
Shimaoka, Motomu
中科院分区：
文献类型：
--
作者：
Peer, Dan;Park, Eun Jeong;Shimaoka, Motomu
细胞周期蛋白 D1 (CyD1) 是一种关键的细胞周期调节分子，也是经过充分研究的癌症治疗靶点。尽管 CyD1 在炎症部位也强烈上调，但其在这种情况下的确切作用仍然未知。为了解决这个问题，我们开发了一种在体内选择性沉默白细胞中 CyD1 的策略。靶向稳定纳米粒子 (tsNPs) 负载有 CyD1 - 小干扰 RNA (siRNA)。然后使用β（7）整合素（β（7）I）抗体来靶向参与肠道炎症的特定白细胞亚群。全身应用 beta(7) I-tsNP 可沉默白细胞中的 CyD1，并通过抑制白细胞增殖和 T 辅助细胞 1 细胞因子表达来逆转实验诱导的小鼠结肠炎。这项研究揭示了 CyD1 是一个潜在的抗炎靶点，并表明在其他治疗环境中应用类似的 siRNA 靶向模式可能是可行的。
Cyclin D1 ( CyD1) is a pivotal cell cycle - regulatory molecule and a well- studied therapeutic target for cancer. Although CyD1 is also strongly up- regulated at sites of inflammation, its exact roles in this context remain uncharacterized. To address this question, we developed a strategy for selectively silencing CyD1 in leukocytes in vivo. Targeted stabilized nanoparticles ( tsNPs) were loaded with CyD1 - small interfering RNA ( siRNA). Antibodies to beta(7) integrin ( beta(7) I) were then used to target specific leukocyte subsets involved in gut inflammation. Systemic application of beta(7) I-tsNPs silenced CyD1 in leukocytes and reversed experimentally induced colitis in mice by suppressing leukocyte proliferation and T helper cell 1 cytokine expression. This study reveals CyD1 to be a potential anti- inflammatory target, and suggests that the application of similar modes of targeting by siRNA may be feasible in other therapeutic settings.