Novel Proteomics Approach to HIV-Associated Neurocognitive Disorder & Drug Abuse

 描述（由申请人提供）：新出现的证据表明，HIV/AIDS和几种形式的药物滥用通过自由基损伤影响大脑，涉及活性氧（ROS，产生氧化应激）和活性氮（RNS），如一氧化氮（NO，产生亚硝化应激）的产生。例如，HIV相关的神经认知障碍（HAND）和甲基苯丙胺似乎都通过氧化和亚硝化应激产生神经元损伤（Cadet和Krasnova，2007）。然而，这种自由基应激的细胞和分子靶点在很大程度上仍然未知。这些未知的蛋白质靶点是该领域的一个主要挑战，需要进行鉴定，以开发疾病的生物标志物，并筛选新的治疗方法，以防止这些靶点被自由基应激破坏。在这里，我提出了一个创新的方法，使用新出现的质谱（MS）技术，以确定翻译后修饰（PTM）的蛋白质产生这样的亚硝化和氧化诱导的氧化还原应激，从而确定新的蛋白质目标艾滋病和药物滥用的影响。因此，由于亚硝化和氧化应激，不可能鉴定经历PTM的全部蛋白质，但新的MS技术应该允许这种鉴定。这些新发现的靶蛋白有望作为疾病过程的生物标志物，也将使我们能够通过发现新的致病途径来指导未来的治疗干预。

 DESCRIPTION (provided by applicant):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.