Toxicoproteomics is the use of global protein expression technologies to gain a better understanding of environmental and genetic factors in stressor exposure and in long term development of disease. The formulation of a strategy to integrate transcript, protein and toxicology data is a major objective for the field of Toxicogenomics. The National Center for Toxicogenomics pursued a strategy of conducting parallel DNA microarray and proteomic analyses on the same tissues from Toxicogenomics studies. The advantage of this approach is to bring more information to bear on toxicological problems in identifying affected, biochemical and regulatory pathways that can lead to biomarker and toxicity signature discovery. Both DNA microarray and proteomic technologies are driven by measuring differential expression of transcripts and proteins after toxicant exposure. The high level of information density and gene discovery potential in microarray analysis can be enhanced by proteomics technologies and supporting bioinformatics databases such as CEBS or chemical effects in biological systems database which now resides at NIEHS. 2D gel and mass spectrometry and surface retentate mass spectrometry or surface enhanced laser desorption ionization, SELDI, were used by the Proteomics Group for serum biomarker development and classification of control and toxicant-exposed experimental animals and also in clinical studies. A primary goal has been biomarker development in liver and serum using proteomic approaches in response to hepatotoxic chemicals. A second area of progress has been in conducting parallel genomic and proteomic studies to compare gene and protein expression. A third area of development has been in serum biomarker development using the SELDI platform in experimental animal studies and in patients with documented clinical disease. Proteomics projects involved study of acetaminophen hepatotoxicity and a second project focused upon the model inflammagen, lipopolysacharide, and its ability to simulate systemic inflammation that could occur during organ injury such as liver necrosis by acetaminophen. hepatotoxicity. The SELDI or surface enhanced laser desorption ionization mass spectrometry has been a relatively new proteomic platform best applied to protein profiling of serum from diseased patients. A proof of principle study was performed using serum from rats acutely exposed to the TLR4 agonist, lipopolysaccharide (LPS). A second SELDI study has been completed on human serum samples from control and diagnosed patients with amyelotrophic lateral sclerosis (ALS) in collaboration with Freya Kamel and Jack Taylor of the Epidemiology branch. The lab work has been completed and the data are undergoing analysis for predictive value in a masked set of normal and ALS patients. A third study was conducted in collaboration with Drs. Russo and Watkins at UNC and the NIEHS Microarray Center. The lab work has been completed and the data are currently have been analyzed within the Microarray Group. Potential serum biomarkers of underlying liver necrotic events were uncovered from rodent studies and human exposure to acetaminophen.
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