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Project 3: Cellular Effects of Aldehydic Products of Lipid Peroxidation

项目3：脂质过氧化醛产物的细胞效应

基本信息

批准号：
7882605
负责人：
LAWRENCE J. MARNETT
金额：
$ 30.36万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-12 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7882605
关键词：
4 hydroxynonenal Affect Agonist Aldehydes Alkynes Anti-Inflammatory Agents Anti-inflammatory Antioxidants Arts Biochemical Biological Biological Assay Biology Cell Line Cell physiology Cells Chemicals Chemistry DNA DNA Damage Data Set Disease Equipment and supply inventories Gene Expression Genetic Transcription Genomics Glutathione Glycerophospholipids Goals Health Human Hydrogen Peroxide Individual Inflammation Inflammatory Inflammatory Response Interferon Type II Laboratories Lead Lipid Chemistry Lipid Peroxidation Lipids Lipopolysaccharides Luciferases Mass Spectrum Analysis Mediator of activation protein Microarray Analysis Modeling Modification Mutagenesis Nonesterified Fatty Acids Outcome Oxidants Pathway Analysis Pathway interactions Pattern Phosphotransferases Physiological Post-Translational Protein Processing Proteins Proteomics RNA Reagent Reporter Research Research Personnel Resources Role Series Signal Pathway Signal Transduction Small Interfering RNA Stress System TP53 gene Technology Testing Toxic effect Toxicity Tests base cytotoxic human disease interest link protein macrophage novel strategies oxidation programs protein expression protein profiling research study response thioredoxin reductase tool transcription factor uptake vector

项目摘要

Emerging evidence from several laboratories indicates that lipid oxidation products make major contributions to human disease. An important class of lipid oxidation products are electrophiles that react with cellular nucleophiles including glutathione, proteins, and DNA. Although glutathione and DMA modification has been studied for many years, inadequate technology has limited our ability to investigate protein modification and its relation to biological outcome. Technological advances in proteomics and genomics now make it possible to assemble comprehensive profiles of proteins modified by lipid electrophiles as well as the transcriptional changes they induce. Comparison of these dense datasets using systems approaches enables hypotheses to be generated linking protein modification to cellular response. Research in the Program Project over the past two years has generated critical reagents and novel approaches for identifying lipid electrophilemodified proteins and their biological consequences. We are now poised to mount an aggressive campaign to define the chemistry and biology of protein modification by lipid electrophiles and its relationship to inflammation, a major contributor to many human diseases. The role of Project 3 is to identify the most biologically interesting lipid electrophiles emanating from research in Projects 1 and.2 and to define the transcriptional changes that they induce in the human macrophage cell line, THP-1. This information will be compared to the pattern of protein modification by the same agents, which will be determined in Project 4, and hypotheses formulated linking protein modification to biological outcome. These hypotheses will be tested using a combination of approaches such as RNA knockdown, ectopic protein expression, and biochemical assays. This will enable the elucidation of mechanisms by which protein modifications by lipid lectrophiles lead to pro- and anti-inflammatory responses.

来自几个实验室的新证据表明，脂质氧化产物起到了重要作用。人类疾病。一类重要的脂类氧化产物是与细胞发生反应的亲电体。包括谷胱甘肽、蛋白质和DNA在内的亲核试剂。尽管谷胱甘肽和DMA修饰已经被经过多年的研究，不充分的技术限制了我们研究蛋白质修饰和它与生物学结果的关系。蛋白质组学和基因组学的技术进步使这一点成为可能组装脂类亲电体修饰的蛋白质的全面图谱以及转录它们所引发的变化。使用系统方法对这些密集数据集进行比较使假设成为可能将蛋白质修饰与细胞反应联系起来。项目实施过程中的问题研究在过去的两年里，产生了关键的试剂和新的方法来鉴定经亲电修饰的脂类蛋白质及其生物学后果。我们现在准备发动一场咄咄逼人的战役定义脂类亲电体修饰蛋白质的化学和生物学及其与炎症，许多人类疾病的主要贡献者。项目3的作用是确定最多从项目1和2的研究中发出的具有生物学意义的脂类亲电体，并定义它们在人巨噬细胞系THP-1中诱导的转录变化。这一信息将是与将在项目4中确定的相同试剂的蛋白质修饰模式相比，并提出了将蛋白质修饰与生物结果联系起来的假设。这些假设将是使用多种方法进行测试，例如RNA敲除、异位蛋白表达和生化分析。这将有助于阐明蛋白质被脂质修饰的机制嗜电者会导致促炎和抗炎反应。