Allele-Specific Effects of Extracellular Superoxide Dismutase on Expression and Disease Susceptibility

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dc.contributor.advisorLadislav Dory
dc.creatorJun, Sujung
dc.date.accessioned2019-08-22T21:28:49Z
dc.date.available2019-08-22T21:28:49Z
dc.date.issued2010-12-01
dc.date.submitted2013-05-02T13:18:50-07:00
dc.description.abstractOur lab previously reported a new allele for extracellular superoxide dismutase (ecSOD), expressed in 129P3/J mice (129), which differs from the wild-type, expressed in C57BL/6J and other strains. The newly discovered allele is associated with significantly increased circulating and heparin-releasable ecSOD activity and amount. To examine the properties of the two forms of ecSOD in an identical environment, I have generated congenic mice expressing either ecSOD allele on C57BL/6 genomic background. The congenic mice plasma ecSOD phenotypes show the same differences reported in the founder mice, indicating that the ecSOD genotype is largely responsible for the observed differences in the ecSOD phenotypes of the C57 and 129 strains. Tissue enzyme distribution of 129 allele is associated with higher levels of enzyme in most tissues; despite profoundly lower levels of the corresponding mRNA levels in the tissues. These results also suggest significant allele-specific differences in the regulation of ecSOD synthesis and intracellular processing/secretion of ecSOD. The increased rates of synthesis and secretion of 129 ecSOD relative to wt ecSOD is confirmed by using stably transfected CHO cells with either of ecSOD allele. The effects of the increased ecSOD levels in tissues on the susceptibility to asbestos-induced lung injury as well as bacterial infections were also investigated in congenic mice. Accordingly congenic mice with the 129 allele were significantly resistant to asbestos-induced fibrosis and injury. On the other hand, the expression of 129 allele significantly aggravated susceptibility to Listeria and Streptococcus infection compared to C57 allele and ecSOD KO mice, suggesting that ecSOD plays an important role in the modulation of immune responses triggered by bacterial infection. Overall this study confirmed the ecSOD allele-specific effects on the ecSOD phenotype and on the disease susceptibilities. In conclusion, the congenic mice offer an excellent model to examine the regulatory mechanisms of ecSOD expression and the role of ecSOD in various diseases involving oxidative stress.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/20.500.12503/29363
dc.language.isoen
dc.provenance.legacyDownloads280
dc.subjectEpidemiology
dc.subjectGenetics
dc.subjectMedicine and Health Sciences
dc.subjectecSOD
dc.subjectpolymorphism
dc.subject129p3/J
dc.subjectcongenic mice
dc.subjectprotein synthesis
dc.subjectdisease susceptibility
dc.titleAllele-Specific Effects of Extracellular Superoxide Dismutase on Expression and Disease Susceptibility
dc.typeDissertation
dc.type.materialtext
thesis.degree.departmentGraduate School of Biomedical Sciences
thesis.degree.disciplineBiochemistry and Molecular Biology
thesis.degree.grantorUniversity of North Texas Health Science Center at Fort Worth
thesis.degree.nameDoctor of Philosophy

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