全身性白细胞导向的小干扰RNA递送揭示细胞周期蛋白D1作为抗炎靶点。
Systemic leukocyte-directed siRNA delivery revealing cyclin D1 as an anti-inflammatory target.
作者信息
Peer Dan, Park Eun Jeong, Morishita Yoshiyuki, Carman Christopher V, Shimaoka Motomu
机构信息
Immune Disease Institute and Department of Anesthesia, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
出版信息
Science. 2008 Feb 1;319(5863):627-30. doi: 10.1126/science.1149859.
Abstract
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.
摘要
细胞周期蛋白D1（CyD1）是一种关键的细胞周期调节分子，也是一个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不清楚。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。靶向稳定纳米颗粒（tsNPs）装载了CyD1小干扰RNA（siRNA）。然后使用β7整合素（β7I）抗体来靶向参与肠道炎症的特定白细胞亚群。全身应用β7I-tsNPs可使白细胞中的CyD1沉默，并通过抑制白细胞增殖和辅助性T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。
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本文引用的文献
1
Utilizing RNA interference to enhance cancer drug discovery.利用RNA干扰技术促进癌症药物研发。
Nat Rev Drug Discov. 2007 Jul;6(7):556-68. doi: 10.1038/nrd2355.
2
Wnt pathway-related gene expression during malignant progression in ulcerative colitis.溃疡性结肠炎恶性进展过程中Wnt信号通路相关基因的表达
Acta Histochem. 2007;109(4):266-72. doi: 10.1016/j.acthis.2007.02.007. Epub 2007 Apr 18.
3
Selective gene silencing in activated leukocytes by targeting siRNAs to the integrin lymphocyte function-associated antigen-1.通过将小干扰RNA靶向整合素淋巴细胞功能相关抗原-1在活化白细胞中实现选择性基因沉默。
Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4095-100. doi: 10.1073/pnas.0608491104. Epub 2007 Feb 28.
4
Targeted delivery of antisense oligodeoxynucleotide and small interference RNA into lung cancer cells.将反义寡脱氧核苷酸和小干扰RNA靶向递送至肺癌细胞。
Mol Pharm. 2006 Sep-Oct;3(5):579-88. doi: 10.1021/mp060039w.
5
Running interference: prospects and obstacles to using small interfering RNAs as small molecule drugs.进行干预：将小分子干扰RNA用作小分子药物的前景与障碍
Annu Rev Biomed Eng. 2006;8:377-402. doi: 10.1146/annurev.bioeng.8.061505.095848.
6
Progress towards in vivo use of siRNAs.小干扰RNA（siRNA）体内应用的研究进展。
Mol Ther. 2006 Apr;13(4):644-70. doi: 10.1016/j.ymthe.2006.01.001. Epub 2006 Feb 14.
7
Differential regulation of D-type cyclins in the mouse intestine.小鼠肠道中D型细胞周期蛋白的差异调节
Cell Cycle. 2006 Jan;5(2):180-3. doi: 10.4161/cc.5.2.2306. Epub 2006 Jan 16.
8
Efficient delivery of small interfering RNA to bone-metastatic tumors by using atelocollagen in vivo.在体内使用去端肽胶原蛋白将小干扰RNA有效递送至骨转移性肿瘤。
Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12177-82. doi: 10.1073/pnas.0501753102. Epub 2005 Aug 9.
9
Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs.化学修饰的小干扰RNA在体内具有强大且持久的抗乙肝病毒活性。
Nat Biotechnol. 2005 Aug;23(8):1002-7. doi: 10.1038/nbt1122. Epub 2005 Jul 24.
10
Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors.通过细胞表面受体介导的小干扰RNA体内抗体递送。
Nat Biotechnol. 2005 Jun;23(6):709-17. doi: 10.1038/nbt1101. Epub 2005 May 22.
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