Date of Award

Fall 12-22-2010

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Graduate Group

Neuroscience

First Advisor

Dr. Kelly L. Jordan-Sciutto

Abstract

HIV-associated neurocognitive disorders (HAND) are comprised of a host of behavioral, cognitive, and motor disabilities and can range from more minor disorders that largely allow basic daily functioning to severe disorders, such as HIV-associated dementia. The mechanisms that ultimately result in neuronal death in HAND are not known. Presented here are data demonstrating activation of the Integrated Stress Response (ISR) in cortical autopsy tissue from HAND patients, as well as data characterizing the nature of the activation of this cellular stress response in this disease. Specifically, we have shown that there are increased levels of the molecular chaperone protein, BiP, which serves as an indicator of general ISR activation. We then present data to suggest that, of the three prongs of the ISR, the prong initiated by ATF6 appears to be active, while PERK does not appear to initiate the prong it regulates. However, intriguingly, proteins downstream of PERK, namely global pEIF2α and astrocytic ATF4 do appear to be activated, suggesting that other initiators outside of the PERK pathway may be acting on these classic components of the ISR. Finally, we show data suggesting that Nrf2, the master regulator of the endogenous antioxidant component of the ISR, may be active in the cortex of HAND patients. While the ISR is clearly a protective response, able to help individual cells protect themselves from toxic insults, it is also able to initiate cellular apoptosis, which in principle protects healthy cells from a dangerous necrotic death of neighboring cells. However, under conditions of chronic stress in the CNS, such as that seen in HAND, too many neurons may die as a result of ISR-initiated apoptosis, thereby resulting in the neurocognitive decline with which these patients are afflicted. Thus, the findings presented here provide starting points of investigation for research aimed at developing potential therapeutic targets for HAND, with some targets for which their response must be increased by therapies and other targets for which their response must be dampened by therapies.

Files over 3MB may be slow to open. For best results, right-click and select "save as..."

Share

COinS