Development and application of mass spectrometry proteomics approaches to study the molecular mechanism of drug-induced skin toxicity

质谱蛋白质组学方法的开发和应用研究药物引起的皮肤毒性的分子机制

• 批准号: 250213-2009
• 负责人: Klarskov, Klaus
• 金额: $ 1.82万
• 依托单位: Université de Sherbrooke
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2011
• 资助国家: 加拿大
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=479521
• 关键词: Development; application; mass; spectrometry; proteomics

Secondary reactions to drugs represent a class of diseases that are often neglected in the clinic and therefore rarely registered. Despite that symptoms may cease when the treatment is interrupted, their significance has been emphasized in a recent report to be among the top six leading causes of fatality. Owing to a continuous increase in consummation and extensive variety of drugs available on the market, such reactions are prone to become a serious problem for the society. Surprisingly many allergic skin reactions are caused by the ingestion of numerous drugs. It is believed that, for a drug to cause an immune-mediated secondary reaction, at least two major events have to take place. First, the drug must be converted into a reactive compound that can modify essential macromolecules such as proteins. Secondly, a cellular stress should be present. This may be caused by either up or down regulation of cellular proteins or by differential post translational modification. While information about the proteins that are targeted in these processes is a crucial step in understanding the molecular mechanism behind secondary drug reactions, only limited data have so far been obtained. This has mainly been due to a lack of sensitive analytical approaches. However, with recent progress in electrophoresis, nanoliquid chromatography and state-of-the-art mass spectrometry, the techniques required are available but innovative approaches need to be developed and evaluated. Therefore, new strategies based on mass spectrometry and modern separation methods will be developed and applied to study the mechanism of immune-mediated adverse skin reactions caused by reverse transcription inhibitor drugs. These are drugs that are widely used for treatment of patients infected with human immunodeficiency virus. In certain cases up to 16% of these patients develop skin allergy reactions that in severe cases result in death. The new strategies that will be developed and applied are anticipated to become important tools to advance our knowledge about the mechanisms involved in drug induced adverse skin reactions.

药物继发反应是临床上经常被忽视的一类疾病，因此很少登记。尽管当治疗中断时症状可能会消失，但最近的一份报告强调了其重要性，将其列为六大致死原因之一。由于不断增加的完善和市场上的药物种类繁多，这种反应往往成为一个严重的社会问题。令人惊讶的是，许多过敏性皮肤反应是由摄入许多药物引起的。据信，一种药物要引起免疫介导的继发反应，至少要发生两个主要事件。首先，药物必须转化为一种反应性化合物，可以改变蛋白质等基本大分子。第二，细胞压力应该存在。这可能是由细胞蛋白质的上调或下调或由差异翻译后修饰引起的。虽然有关这些过程中靶向蛋白质的信息是了解继发性药物反应背后分子机制的关键一步，但迄今为止只获得了有限的数据。这主要是由于缺乏敏感的分析方法。然而，随着电泳，纳米液体色谱和国家的最先进的质谱的最新进展，所需的技术是可用的，但创新的方法需要开发和评估。因此，将开发并应用基于质谱和现代分离方法的新策略来研究逆转录抑制剂药物引起免疫介导的皮肤不良反应的机制。这些药物被广泛用于治疗感染人类免疫缺陷病毒的患者。在某些情况下，这些患者中高达16%会发生皮肤过敏反应，严重时会导致死亡。预计将开发和应用的新策略将成为推进我们对药物引起的不良皮肤反应机制的认识的重要工具。