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Targeting Transcription Factor NF-kappa B by Dual Functional Oligodeoxynucleotide Complex for Inhibition of Neuroinflammation

Hu, Jing
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439301618

Abstract Details

2015, PhD, University of Cincinnati, Pharmacy: Pharmaceutical Sciences/Biopharmaceutics.
Because transcription factor nuclear factor (NF)- κB plays an important role in vascular inflammation at blood-brain barrier, the present study constructed a novel DNA complex to specifically target endothelial NF-κB for inhibition of cerebral inflammation. This DNA complex (GS24-NFκB) contains two functional domains: a DNA Decoy for inhibiting NF-κB activity and a DNA aptamer (GS-24), a ligand of transferrin receptor (TfR), for targeted delivery of the DNA Decoy into brain endothelial cells. The results indicated that GS24-NFκB was delivered into murine brain-derived endothelial (bEnd5) cells and the delivery was specific and TfR-dependent. The DNA chimera inhibited inflammatory responses in the cells induced by tumor necrosis factor a (TNF-α) or oxygen-glucose deprivation/reoxygenation (OGD/R) via down-regulation of nuclear NF-κB subunit, P65, as well as its downstream inflammatory cytokines, such as inter cellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1). The anti-inflammatory effect of the GS24-NFκB was shown as significant reduction in monocyte adhesion to the bEnd5 cells induced by TNF-a or OGD/R after GS24-NFκB treatment. Pharmacokinetic study suggested its poor nuclease resistance and rapid clearance from systemic circulation. Organ uptake of GS24-NFκB including brain uptake was much higher compared to the scramble control and high organ uptake was observed in liver and spleen with high expression of TfR. The brain uptake is 0.39%ID/g, which is comparable to the brain uptake of anti-TfR monoclonal antibody, OX26 (0.44%ID/g). Intravenous injection of GS24-NFκB (15mg/kg) was able to significantly reduce the expressions of phospho-P65 and VCAM-1 in brain endothelial cells in mouse lipopolysaccharide (LPS) induced inflammatory model, suggesting effective inhibition of activation and transcriptional activity of NF-κB. However, the disease-modifying effects of GS24-NFκB need to be further investigated in future. In conclusion, our approach using DNA nanotechnology has successfully delivered the therapeutic decoy into brain endothelial cells and induce pharmacological effect. It could be potentially applied for inhibition of inflammation in ischemic stroke and other neuroinflammatory diseases affecting cerebral vasculature.
Jiukuan Hao, Ph.D. (Committee Chair)
Gary Gudelsky, Ph.D. (Committee Member)
Kevin Li, Ph.D. (Committee Member)
Giovanni Pauletti, Ph.D. (Committee Member)
Kim Seroogy, Ph.D. (Committee Member)
96 p.
Pharmaceuticals
neuroinflammation; NF-kappa B decoy; GS24 aptamer; ICAM-1; VCAM-1

Recommended Citations

Citations

  • Hu, J. (2015). Targeting Transcription Factor NF-kappa B by Dual Functional Oligodeoxynucleotide Complex for Inhibition of Neuroinflammation [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439301618

    APA Style (7th edition)

  • Hu, Jing. Targeting Transcription Factor NF-kappa B by Dual Functional Oligodeoxynucleotide Complex for Inhibition of Neuroinflammation. 2015. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439301618.

    MLA Style (8th edition)

  • Hu, Jing. "Targeting Transcription Factor NF-kappa B by Dual Functional Oligodeoxynucleotide Complex for Inhibition of Neuroinflammation." Doctoral dissertation, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439301618

    Chicago Manual of Style (17th edition)

ucin1439301618
442
© 2015, some rights reserved.Creative Commons License Targeting Transcription Factor NF-kappa B by Dual Functional Oligodeoxynucleotide Complex for Inhibition of Neuroinflammation by Jing Hu is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by University of Cincinnati and OhioLINK.