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Hynes, SO,McCabe, C,O'Brien, T,McCarthy, HO,Coulter, JA
2011
April
Methods Mol Biol
beta Cell Protection by Inhibition of iNOS Through Lentiviral Vector-Based Strategies
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Diabetes mellitus pancreatic islet cells iNOS small interfering RNAs NF-kappa B gene silencing gene therapy NITRIC-OXIDE SYNTHASE PANCREATIC-ISLETS RNA INTERFERENCE DIABETES-MELLITUS INSULINOMA CELLS GENE-EXPRESSION GRAFT-SURVIVAL NOD MICE TRANSPLANTATION TRANSDUCTION
704
153
168
Cytoprotective gene transfer to pancreatic islet beta cells may prove useful in preventing their destruction and prolonging islet graft survival after transplantation in patients with type 1 diabetes mellitus. A host of therapeutically relevant transgenes may potentially be incorporated into an appropriate gene delivery vehicle and used for islet modification. To examine this, we utilised a robust model of cytokine-induced beta cell pathophysiology. Using this model, it is clear that antioxidant gene transfer confers no cytoprotective benefit. In contrast, we demonstrated that gene-based approaches to inhibit the activation of NF-kappa B following cytokine exposure harbours therapeutic utility in preserving islet beta cell viability in the face of cytokine toxicity. We identified that NF-kappa B-dependent induction of iNOS is a critical determinant of beta cell fate following cytokine exposure. Having identified the pivotal role of iNOS activation in cytokine-induced beta cell pathophysiology, lentiviral vectors may be used to efficiently deliver small interfering RNA molecules to confer efficient iNOS gene silencing. We have shown that lentiviral vector-based shRNA delivery holds significant promise in preserving beta cell viability following cytotoxic cytokine exposure.
10.1007/978-1-61737-964-2_12
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