Discovery of phosgene and chlorine gas modes of action and therapeutic targets using chemoproteomic profiling strategies

使用化学蛋白质组学分析策略发现光气和氯气的作用模式和治疗靶点

• 批准号: 10883970
• 负责人: Satyanarayana Achanta
• 金额: $ 49.42万
• 依托单位: BATTELLE PACIFIC NORTHWEST LABORATORIES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-19 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10883970
• 关键词: Active Sites; Acute; Acute Lung Injury; Acylation; Affect; Animal Model; Antidotes; Binding Sites; Biochemical; Bioinformatics; Biological Markers; Biology; Cell physiology; Chemical Injury; Chemicals; Chlorine; Cysteine; Data; Development; Event; Exposure to; Family suidae; Functional disorder; Future; Gases; Hydrolysis; Industrialization; Inhalation; Label; Ligand Binding; Lipids; Lung; Maps; Mass Spectrum Analysis; Military Personnel; Modification; Molecular; Molecular Analysis; Molecular Target; Mus; Nature; Oxidation-Reduction; Oxidative Stress; Oxidative Stress Induction; Pathway Analysis; Pathway interactions; Phosgene; Physiology; Post-Translational Protein Processing; Predisposition; Protein Analysis; Proteins; Proteome; Proteomics; Reaction; Research; Role; Sampling; Site; Structure of parenchyma of lung; Therapeutic; Time; Tissues; Toxic effect; Toxicant exposure; Toxicology; Universities; cell injury; chemical threat; chemoproteomics; chlorine gas; data integration; design; experience; functional loss; lung injury; multidisciplinary; occupational hazard; oxidation; protein complex; protein function; therapeutic development; therapeutic target; toxicant

Project Summary: Phosgene and chlorine are two toxic gases produced on large industrial scales that pose occupational hazards and chemical threats to the public and military. Both toxicants modify proteins in various ways and induce oxidative stress in the lung which perturb critical functions and pathways. However, the precise nature and sites of these modifications in the lung proteome have not been identified, and the potential chemical diversity of these modifications poses an analytical challenge to unraveling the molecular mechanisms by which chlorine and phosgene induce acute lung injury. This lack of biomolecular characterization of phosgene- and chlorine-induced modification of protein targets has consequently hindered our ability to develop effective countermeasures; there are currently no approved therapeutics for treating phosgene or chlorine gas exposures. We propose to use chemoproteomic profiling—a subset of mass spectrometry-based proteomics that can detect the sites and types of distinct chemical modifications to proteins—to comprehensively identify specific proteins in the lung that have been chemically altered by phosgene and chlorine and perform pathway analysis to identify protein candidates for future targeted countermeasure development. The specific aims of this proposal are: Aim 1: Dynamic redox profiling to identify the temporal protein cysteine oxidation events and global proteome changes following gaseous toxicant exposure Aim 2: Mapping phosgene- and chlorine-induced protein modifications in the lung using electrophilic chemical probes Aim 3: Data integration and network analysis to identify shared and unique molecular targets of phosgene and chlorine for therapeutic development

项目摘要： 磷酸和氯是在大型工业尺度上产生的两种有毒气体，构成造成危害 以及对公共和军事的化学威胁。两种毒物都以各种方式和影响来修饰蛋白质 肺中的氧化应激，肺部临界功能和途径。但是，精确性和 尚未鉴定出肺蛋白质组中这些修饰的位点，并且潜在的化学多样性 在这些修饰中，构成了分析机制的分析挑战 氯和磷诱导急性肺损伤。缺乏磷烯和 因此，氯引起的蛋白质靶标的修饰已阻碍我们发展有效的能力 对策；目前尚无批准治疗磷酸或氯气的疗法 暴露。我们建议使用化学蛋白质组学分析 - 基于质谱的蛋白质组学的子集 可以检测到对蛋白质的不同化学修饰的位点和类型，以全面识别 肺中的特定蛋白质已被磷和氯化学改变并执行途径 分析以识别候选蛋白质的未来对策开发。 该提案的具体目的是： AIM 1：动态氧化还原分析以识别临时蛋白质半胱氨酸氧化事件和全局蛋白质组 气体毒物暴露后的变化 AIM 2：使用亲电化学化学绘制肺中的磷酸和氯诱导的蛋白质修饰 问题 目标3：数据集成和网络分析，以识别Phosgene的共享和独特的分子靶标 治疗发育的氯