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: 9249520
• 负责人: STUART A LIPTON
• 金额: $ 62.35万
• 依托单位: SCINTILLON INSTITUTE FOR PHOTOBIOLOGY
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9249520
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Affect; Anti-HIV Agents; Biological Markers; Brain; Dementia; Disease; Drug abuse; Free Radicals; Future; Generations; HIV-associated neurocognitive disorder; Impaired cognition; Lead; Mass Spectrum Analysis; Methamphetamine; Modeling; Molecular Target; Neurons; Nitric Oxide; Oxidation-Reduction; Oxidative Stress; Pathogenicity; Pathway interactions; Patients; Post-Translational Protein Processing; Process; Proteins; Proteomics; Reactive Nitrogen Species; Reactive Oxygen Species; Stress; Techniques; Therapeutic Intervention; Work; cellular targeting; heuristics; innovation; nitrosative stress; novel; novel therapeutics; prevent; public health relevance; screening; therapeutic target

 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（应用程序提供）：新兴证据表明，启发式模型表明，艾滋病毒/艾滋病和几种形式的药物滥用都会通过自由基损伤来影响大脑，涉及产生活性氧（ROS，产生氧化物胁迫）和活性氮（RNS），例如硝酸氧化物（NO，导致硝化剂量）。例如，与HIV相关的神经认知障碍（手）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 and Krasnova，2007）。但是，这种自由基应力的细胞和分子靶标在很大程度上未知。这些未知的蛋白质靶标是该领域的主要挑战，需要确定既开发疾病的生物标志物，并允许对新疗法进行筛查，以防止通过自由基压力来防止这些靶标的腐败。在这里，我提出了一种使用新出现的质谱法（MS）技术的创新方法，以鉴定由于这种硝化剂和氧化诱导的氧化还原胁迫而产生的蛋白质翻译后修饰（PTM），从而确定了艾滋病和药物滥用影响的新蛋白质靶标。迄今为止，由于亚硝化应力和氧化应激，无法识别出PTM的全范围，但是新的MS技术应允许这种鉴定。这些新鉴定的靶蛋白有望用作疾病过程的生物标志物，也应该使我们能够通过发现新的病原途径来指导未来的治疗干预措施。