Emerging evidence suggests the heuristic model that both HIV/AIDS and several forms of drug abuse affect the brain via free radical damage involving the generation of reactive oxygen species (ROS, producing oxidative stress) and reactive nitrogen species (RNS) such as nitric oxide (NO, resulting in nitrosative stress). For example, both HIV- associated neurocognitive disorder (HAND) and methamphetamine appear to produce neuronal damage via oxidative and nitrosative stress (Cadet and Krasnova, 2007). However, the cellular and molecular targets of this free radical stress remain largely unknown. These unknown protein targets are a major challenge for the field and need to be identified in order to develop both Biomarkers of disease and to allow screening for new therapies to prevent corruption of these targets by free radical stress. Here, I propose an innovative approach using newly emerging Mass Spectrometry (MS) techniques to identify the posttranslational modifications (PTMs) of proteins resulting from such nitrosative- and oxidative-induced redox stress and hence identify new protein targets affected by AIDS and drug abuse. Heretofore, it has not been possible to identify the full range of proteins undergoing PTMs due to nitrosative and oxidative stress, but new MS techniques should allow this identification. These newly identified target proteins are expected to serve as Biomarkers of the disease process and also should allow us to direct future therapeutic intervention by discovering new pathogenic pathways.
Mild cognitive decline that can lead to frank dementia is commonly associated with AIDS and known as HIV-associated neurocognitive disorder (or HAND). Drug abuse, particularly with methamphetamine, is often encountered as a co-morbid condition in patients with HAND. Here, we propose an innovative approach using newly emerging Mass Spectrometry (MS) techniques to identify modifications of proteins caused by free radical damage resulting from AIDS and drug abuse. This work will identify aberrant protein modifications effected by HAND and drug abuse, and thus new potential therapeutic targets as well as biomarkers of the disease process.
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