Date of Award

8-1-2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Biomedical Sciences

Department

Graduate School of Biomedical Sciences

First Advisor

Anuja Ghorpade

Second Advisor

Robert Luedtke

Third Advisor

Porunelloor A. Mathew

Abstract

Despite the advent of antiretroviral therapy (ART), central nervous system (CNS) complications associated with HIV-1 infection, collectively referred to as HIV-associated neurocognitive disorders (HAND), continue to increase. HIV infection promotes cognitive dysfunction and neurodegeneration through persistent inflammation, oxidative stress from infected and/or activated macrophages, astrocytes and neurons. Additionally, recent studies demonstrated that neurotoxic side effects of antiretroviral (ARV) drugs are among several contributing factors to this continued prevalence of HAND. In recent years, a new appreciation of the role of astrocytes in regulating HIV-1 CNS infection has emerged. Thus, investigating the elusive cellular and molecular mechanisms regulated by astrocytes during HIV-1/ART-induced neurotoxicity could provide insight into HAND pathogenesis. The work presented in this thesis contributes to the documentation of astrocyte dysfunction in HIV-1-infection. The accumulated data reveal the multifaceted mechanisms and roles of astrocytes in HIV-1 CNS infection. A neuropathological feature of HIV-1 infection includes reactive astrogliosis, which is a hallmark of many neurodegenerative diseases. Our studies reveal the regulation of β-catenin signaling on major aspects of reactive astrogliosis i.e., proliferation, wound healing and inflammation. HAND-relevant inflammatory stimuli activate β-catenin signaling in astrocytes. Our in vitro studies reveal knockdown of β-catenin impairs astrocyte responses to injury. Further, reduced levels of β-catenin also show less proliferation and inflammatory responses in astrocytes. We also demonstrated that Wnt/ β-catenin and NF-κB crosstalk links with inflammation during HIV-1 CNS infection. We next investigated endoplasmic reticulum (ER) stress associated with HAND-relevant neuroinflammation. Our studies show that ART (abacavir) and interleukin-1β increase cytosolic calcium in astrocytes, which in turn regulates ER stress and mitochondrial depolarization. We also identify astrocyte elevated gene (AEG)-1 as an ER stress inducible gene. In addition, AEG-1 interacts with calnexin, which emphasizes AEG-1 as a scaffolding protein regulating ER calcium signaling. Further, HIV-1-coupled inflammation and oxidative stress significantly increase regulator of ribosome synthesis (RRS1) expression, suggesting inhibition of rRNA transcription in astrocytes. Further, AEG-1 overexpression enhanced oxidative stress-induced RRS1 expression, i.e., nucleolar stress in astrocytes. Taken together, this study identified novel regulatory mechanisms in reactive astrocytes during HIV-1-induced neurodegeneration that might serve as innovative therapeutic targets for HAND.

Comments

Shruthi Nooka, Uncovering the Multifaceted HAND of Reactive astrocytes in HIV-Associated Neurocognitive Disorders Doctor of Philosophy (Biomedical Sciences), July 2017, 149 pp., 304 bibiliographies.

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