Astrocyte Elevated Gene-1, a Novel Modulator of Astrocyte Function: Implications for neuroAIDS, aging and glioblastoma

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dc.contributor.advisorGhorpade, Anuja
dc.creatorVartak, Neha
dc.date.accessioned2019-08-22T21:11:15Z
dc.date.available2019-08-22T21:11:15Z
dc.date.issued2013-12-01
dc.date.submitted2013-12-03T09:31:01-08:00
dc.description.abstractVartak-Sharma, Neha N., Astrocyte elevated gene-1, a novel modulator of astrocyte function: Implications for NeuroAIDS, aging and glioblastoma. Doctor of Philosophy (Biomedical Sciences), Nov, 2013, 180 pp., 1 table, 40 illustrations, 336 bibliographies. Recent attempts to analyze human immunodeficiency virus (HIV)-1-induced gene expression changes in astrocyte identified a multifunctional oncogene, astrocyte elevated gene-1 (AEG-1), as an HIV-1 and tumor necrosis factor-inducible transcript. Subsequently, due to its homology to mouse breast cancer metastasis protein, metadherin, AEG-1 was largely implicated in carcinogenesis of diverse cancer types. However, the role of AEG-1 in astrocytes, the original cell type in which AEG-1 was first identified, still remains to be investigated. In the present study, we identified AEG-1 as a novel modulator of astrocyte function during reactive astrogliosis, neuroinflammation and neurodegeneration, and elucidated its implications in NeuroAIDS, aging and cancer. Our in vitro and in vivo studies recognized AEG-1 modulation of astrocyte migration and proliferation towards the wound site, thereby regulating astrocyte wound healing, a fundamental homeostatic function of astrocytes. Further, AEG-1 expression analyses in HIV-1+ and HIV-1 encephalitic human brain tissues provided the necessary physiological evidence for AEG-1 induction upon HIV-1 neuroinvasion. Herein, we identified AEG-1 as an inflammatory response gene and as an important upstream regulator of NF-κB signaling in astrocytes. Our results demonstrated AEG-1 cytoplasmic and nuclear interaction with NF-κB p65 subunit, which was crucial for NF-κB nuclear translocation, thereby regulating astrocyte neuroinflammation. In the same study, we also identified AEG-1 as a novel regulator of astrocyte glutamate clearance, an important determinant of neurocognitive CNS function, by modulating the expression of the key glutamate transporter, excitatory amino acid transporter 2. Analyses of AEG-1 expression in the cognitive centers of the brain of aging individuals demonstrated AEG-1 age-dependent expression in the human brain, which further proposed a role for AEG-1 in cellular oxidative stress responses. Herein, we identified a novel antioxidant cytoprotective role of AEG-1 in astrocytes and astrocytoma cells. Cellular localization studies by confocal microscopy revealed AEG-1 localization to the dense fibrillar components of the nucleolus in response to injury or oxidative stress, suggesting AEG-1 implication in ribosomal RNA processing. Our results demonstrated AEG-1 regulation of catalase activation and Nrf2 stabilization in response to oxidative stress and further elucidated AEG-1 modulation of Nrf2 nuclear translocation, the first step in antioxidant cellular defense mechanisms. The results presented in this thesis provide insight into the role of oncogene AEG-1 in human astrocytes and ameliorates our understanding of astrocyte-mediated processes in normal and disease-relevant pathologies, ranging from HIV-1-associated neurocognitive disorders and traumatic CNS injuries to primary neoplasms of the brain.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/20.500.12503/29138
dc.language.isoen
dc.provenance.legacyDownloads55
dc.subjectCancer Biology
dc.subjectCell and Developmental Biology
dc.subjectCells
dc.subjectImmunology and Infectious Disease
dc.subjectMedicine and Health Sciences
dc.subjectOncology
dc.subjectAstrocycte elevated gene-1
dc.subjectHIV
dc.subjectGlioma
dc.subjectneurodegeneration
dc.subjectneuroinflammation
dc.titleAstrocyte Elevated Gene-1, a Novel Modulator of Astrocyte Function: Implications for neuroAIDS, aging and glioblastoma
dc.typeDissertation
dc.type.materialtext
thesis.degree.departmentGraduate School of Biomedical Sciences
thesis.degree.grantorUniversity of North Texas Health Science Center at Fort Worth
thesis.degree.nameDoctor of Philosophy

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