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: 9884749
• 负责人: STUART A LIPTON
• 金额: $ 96.75万
• 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 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884749
• 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; comorbidity; 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(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通过自由基损伤影响大脑，其中包括产生活性氧(ROS，产生氧化应激)和活性氮(RNS)，如一氧化氮(NO，导致亚硝酸盐应激)。例如，艾滋病毒相关的神经认知障碍(手)和甲基苯丙胺似乎都会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不清楚。这些未知的蛋白质靶标是该领域的一个重大挑战，需要确定，以便开发疾病的生物标记物，并允许筛选新的治疗方法，以防止这些靶标因自由基应激而腐败。在这里，我提出了一种创新的方法，使用新出现的质谱学(MS)技术来识别这种亚硝化和氧化诱导的氧化还原应激引起的蛋白质的翻译后修饰(PTM)，从而识别受艾滋病和药物滥用影响的新的蛋白质靶点。到目前为止，还不可能鉴定由于亚硝化和氧化应激而进行PTMS的所有蛋白质，但新的MS技术应该可以进行这种鉴定。这些新发现的靶蛋白有望成为疾病过程的生物标志物，也应该允许我们通过发现新的致病途径来指导未来的治疗干预。