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

治疗 HIV 相关神经认知障碍的蛋白质组学新方法

• 批准号: 9599797
• 负责人: STUART A LIPTON
• 金额: $ 51.83万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9599797
• 关键词: Novel; Proteomics; Approach; HIV; Associated

 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.

 描述（由申请人提供）：新出现的证据表明，艾滋病毒/艾滋病和几种形式的药物滥用都会通过自由基影响大脑，涉及损害活性氧（ROS，产生氧化应激）和活性氮（产生氧化应激）的产生。 RNS），例如一氧化氮（NO，导致亚硝化应激）。例如，HIV 相关神经认知障碍 (HAND) 和甲基苯丙胺似乎都会通过氧化产生神经元损伤。和亚硝化应激（Cadet 和 Krasnova，2007）然而，这种自由基应激的细胞和分子靶标仍然很大程度上未知，这些未知的蛋白质靶标是该领域的主要挑战，需要确定以开发这两种生物标志物。在这里，我提出了一种创新方法，使用新兴的质谱（MS）技术来识别由此类疾病引起的蛋白质翻译后修饰（PTM）。亚硝化和氧化诱导的氧化还原应激，从而识别受艾滋病和药物滥用影响的新蛋白质靶标。 迄今为止，还不可能识别由于亚硝化和氧化应激而经历 PTM 的全部蛋白质，但新的 MS 技术应该允许。这些新鉴定的靶蛋白有望作为疾病过程的生物标志物，并且还应该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。