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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies
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Cell Proliferation
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Colitis / drug therapy*
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Colitis / metabolism
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Colitis / pathology
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Colon / pathology
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Cyclin D
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Cyclins / genetics*
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Cyclins / physiology
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Cytokines / metabolism
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Drug Carriers*
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Genes, bcl-1*
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Hyaluronic Acid
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Inflammatory Bowel Diseases / drug therapy
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Inflammatory Bowel Diseases / immunology
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Inflammatory Bowel Diseases / pathology
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Integrin beta Chains / immunology
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Leukocytes / cytology
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Leukocytes / drug effects*
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Leukocytes / immunology
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Leukocytes / metabolism
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Liposomes
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Mice
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Nanoparticles
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Protamines
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RNA Interference*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / administration & dosage*
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RNA, Small Interfering / chemistry
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RNA, Small Interfering / metabolism
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T-Lymphocytes, Helper-Inducer / immunology
Substances
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Antibodies
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Cyclin D
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Cyclins
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Cytokines
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Drug Carriers
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Integrin beta Chains
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Liposomes
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Protamines
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RNA, Messenger
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RNA, Small Interfering
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integrin beta7
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Hyaluronic Acid