title: β cell protection by inhibition of iNOS through lentiviral vector-based strategies.
abstract: Cytoprotective gene transfer to pancreatic islet β cell s 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 β 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-κBNF-κB following cytokine exposure harbours therapeutic utility in preserving islet β cell viability in the face of cytokine toxicity. We identified that NF-κB-dependent induction of iNOSiNOS is a critical determinant of β cell fate following cytokine exposure. Having identified the pivotal role of iNOS activation in cytokine-induced β cell pathophysiology, lentiviral vectors may be used to efficiently deliver small interfering RNARNA molecules to confer efficient iNOS gene silencing. We have shown that lentiviral vector-based shRNA delivery holds significant promise in preserving β cell viability following cytotoxic cytokine exposure.
authors.affiliation: Regenerative Medicine Institute, National University of Ireland, Galway, Ireland. seanhynes@yahoo.com
authors.forename: Sean O
authors.initials: SO
authors.lastname: Hynes
authors.forename: Cillian
authors.initials: C
authors.lastname: McCabe
authors.forename: Timothy
authors.initials: T
authors.lastname: O'Brien
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology; D019610:Cytoprotection / Q000235:genetics*; D020868:Gene Silencing / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology* / Q000637:transplantation; D016086:Lentivirus / Q000235:genetics*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D052247:Nitric Oxide Synthase Type II