Thayer 2005 Thesis

Thayer TC (2005) Critical role of superoxide production in the pathogenesis of autoimmune diabetes. Thesis University of Pittsburgh, School of Medicine, PhD Thesis: 152pp.

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Thayer (2005) Thesis

Abstract: Type 1 diabetes (T1D), a disease characterized by the autoimmune-mediated destruction of the insulin-secreting beta cells of the pancreas, affects approximately 1% of the US population, with an incidence that is increasing at a rate of 3% per year. Beta cell killing is accomplished through various immune-mediated mechanisms, with the production of reactive oxygen species (ROS) contributing to both inflammation and cell death. While previous reports suggested that antioxidant scavenging protected beta cells against ROS-mediated damage, isletspecific over-expression of antioxidants was not fully protective. As systemic elevation in free radical defenses had a positive impact on islet survival, I hypothesize that control of oxidative stress at the level of the immune system will regulate proinflammatory responses. Genetic studies using the ALR mouse have provided strong support for my hypothesis. ALR-derived diabetes resistance and reduced oxidative burst from neutrophils and macrophages, as well as elevated Superoxide Dismutase 1 (SOD1) activity all map to the Suppressor of superoxide production (Susp) locus on Chr. 3. NAPDH oxidase (NOX) function from ALR cells could be rescued with inhibition of SOD1, demonstrating that dissipation was modifying immune effector function. Elevated SOD1 activity was associated with increased dimer stability, suggesting a post-translational modification is enhancing dimerization. Introduction of Susp into the NOD background was highly protective against T1D. This resistance is linked to the loss of T lymphocyte diabetogenic potential. The loss of T cell ROS in T1D protection was confirmed using NOX-deficient NOD mice. T cell lineage commitment and proinflammatory cytokine synthesis were dependent on ROS signaling. Macrophages and T cells from NOD-Ncf1m1J mice exhibited a skewed cytokine response, with increased synthesis of IL-17 and IL-10, as opposed to the predominant IFN-γ production typically observed from NOD lymphocytes. Genome-wide analyses were performed to fine map Susp in order to define the mechanism leading to altered SOD1 activity. Positional cloning experiments mapped Susp between D3Mit180 (34.4 Mbp) and D3Mit223 (34.8 Mbp) on Chr. 3. This mapping defines a novel candidate region involved in the regulation of SOD1 activity and dimerization stability, resulting in reduced superoxide release via NADPH oxidase activity. • Keywords: Superoxide; Diabetes

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Stress:z edited"z edited" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property., RONS; Oxidative Stress"RONS; Oxidative Stress" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property., Genetic Defect; Knockdown; Overexpression"Genetic Defect; Knockdown; Overexpression" is not in the list (Cell death, Cryopreservation, Ischemia-reperfusion, Permeability transition, Oxidative stress;RONS, Temperature, Hypoxia, Mitochondrial disease) of allowed values for the "Stress" property.  Organism: z edited"z edited" is not in the list (Human, Pig, Mouse, Rat, Guinea pig, Bovines, Horse, Dog, Rabbit, Cat, ...) of allowed values for the "Mammal and model" property., Mouse  Tissue;cell: z edited"z edited" is not in the list (Heart, Skeletal muscle, Nervous system, Liver, Kidney, Lung;gill, Islet cell;pancreas;thymus, Endothelial;epithelial;mesothelial cell, Blood cells, Fat, ...) of allowed values for the "Tissue and cell" property., Islet Cell; Pancreas; Thymus"Islet Cell; Pancreas; Thymus" is not in the list (Heart, Skeletal muscle, Nervous system, Liver, Kidney, Lung;gill, Islet cell;pancreas;thymus, Endothelial;epithelial;mesothelial cell, Blood cells, Fat, ...) of allowed values for the "Tissue and cell" property.  Preparation: Intact Cell; Cultured; Primary"Intact Cell; Cultured; Primary" is not in the list (Intact organism, Intact organ, Permeabilized cells, Permeabilized tissue, Homogenate, Isolated mitochondria, SMP, Chloroplasts, Enzyme, Oxidase;biochemical oxidation, ...) of allowed values for the "Preparation" property.  Enzyme: z in prep"z in prep" is not in the list (Adenine nucleotide translocase, Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase, Inner mt-membrane transporter, Marker enzyme, Supercomplex, TCA cycle and matrix dehydrogenases, ...) of allowed values for the "Enzyme" property.  Regulation: z in prep"z in prep" is not in the list (Aerobic glycolysis, ADP, ATP, ATP production, AMP, Calcium, Coupling efficiency;uncoupling, Cyt c, Flux control, Inhibitor, ...) of allowed values for the "Respiration and regulation" property. 

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