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dc.contributor.advisorCota-Gomez, Adela
dc.contributor.authorSimenauer, Ari M.
dc.contributor.committeememberBeckham, J. David
dc.contributor.committeememberFlores, Sonia
dc.contributor.committeememberSantiago, Mario
dc.contributor.committeememberGrayck, Eva N.
dc.date.accessioned2020-09-14T10:03:30Z
dc.date.available2020-09-14T10:03:30Z
dc.date.issued2020
dc.descriptionIncludes bibliographical references.
dc.descriptionSummer
dc.description.abstractChronic HIV infection in the era of anti-retroviral therapy is associated with dramatically increased risk of developing severe cardio-pulmonary disease. Common to these diseases are increased oxidative burden and chronic inflammation despite low viremia and restoration of CD4+ T-cell levels. Soluble viral factors are heavily implicated in these disease processes, including the HIV Transactivator of Transcription (Tat). Tat is produced in high levels during infection and secreted from infected cells into circulation where it is internalized by bystander cells and is known to regulate inflammatory pathways and elicit a pro-oxidant environment. However, the mechanisms by which Tat induces a pro-oxidant cellular and tissue environment remain poorly described. It has previously been demonstrated that Tat down-regulates transcription of the critical mitochondrial antioxidant enzyme Superoxide Dismutase 2 (SOD2) by altering the binding ratio of the transcription factors Sp1 and Sp3 to the proximal (-210) region of the sod2 promoter. In this work, we have characterized the effect of Tat on Sp1/Sp3 occupancy to the distal sod2 promoter and the resulting effect on SOD2 expression in primary human pulmonary arterial endothelial cells (HPAEC) as well as observed the effect of HIV infection on SOD2 levels in the lungs of HIV infected humanized mice. We found that Tat resulted in increased levels of SOD2, and that this effect was mediated at least in part by direct interaction of Tat with Sp3 resulting in reduced Sp3 occupancy to the distal sod2 promoter. Additionally, HIV infected mice demonstrated markedly increased levels of SOD2 in the lungs as measured by IHC of lungs sections, although reduced total antioxidant capacity in the lungs of infected mice indicate that the lungs of these animals remain oxidatively stressed. Furthermore, we have explored the effects of Tat on the redox regulatory nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which transactivates cytoprotective genes by binding to anti-oxidant response elements (ARE) in their promoter regions. Specifically, we have demonstrated that Tat represses Nrf2/ARE mediated transcription and results in increased levels of cellular and mitochondrial superoxide in a Tat expressing cell line. Tat also repressed basal transcriptional activity of Nr2/ARE driven antioxidant genes in HPAEC and desensitized cells to exogenous chemical stimulation of Nrf2.
dc.format.mediumborn digital
dc.format.mediumdoctoral dissertations
dc.identifierSimenauer_ucdenveramc_1639D_10761.pdf
dc.identifier.urihttps://hdl.handle.net/10968/5754
dc.languageEnglish
dc.publisherUniversity of Colorado at Denver, Anschutz Medical Campus. Health Sciences Library
dc.relation.ispartof2017 to Current
dc.rightsCopyright of the original work is retained by the author.
dc.subject.meshHost-Pathogen Interactions
dc.subject.meshLung Diseases
dc.subject.meshPulmonary Arterial Hypertension
dc.subject.meshInflammation
dc.subject.meshHIV
dc.subject.meshOxidative Stress
dc.titleHIV TAT mediation of redox sensitive transcription factors in pulmonary vascular cells
dc.typeText
thesis.degree.disciplineMicrobiology
thesis.degree.grantorUniversity of Colorado at Denver, Anschutz Medical Campus
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)


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