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151 Wistar Institute
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Our research group primarily focuses on proteomics of human diseases and structure-function of protein-protein interactions. We are currently pursuing two structure-function projects that primarily utilize biophysical methods, such as isothermal titration calorimetry and sedimentation equilibrium, and mass spectrometry to probe protein structures, protein-protein interactions and function. One project involves the giant membrane skeletal protein spectrin, a human actin crosslinking protein that plays a key role in stabilizing the plasma membrane in most cell types. Current studies focus on the proteotypical spectrin tetramers found in human red blood cells and their role in membrane purturbations caused by hereditary hemolytic anemia mutations. Another project involves structure-function analysis of peroxiredoxin 6, an antioxidant enzyme with glutathione peroxidase activity and phospholipase activity, which plays a critical role in protecting lung and other tissues from damage due to oxidative stress. Our proteomics projects involve four major research areas. One project uses comprehensive protein profiling methods and pathway/network analyses to identify key mechanisms associated with development of metastatic potential in human cancers. A second group of projects uses a mass spectrometry/bioinformatics strategy to discover human biomarkers of several different types of cancers in mouse models with subsequent quantitative validation of candidate biomarkers in patients. A third project involves the direct analysis of patients' serum samples using high throughput mass spectrometry-based methods to discover protein patterns that correlate with human pregnancy disorders. This project also involves development of superior high throughput serum protein profiling methods, including new analytical separation strategies and new computational tools for data analysis and biomarker pattern recognition. The fourth proteomics project investigates the role of oxidative stress in development of acute lung injury utilizing mouse models and human plasma samples. Selected Publications: Wu, Y., Feinstein, S.I., Manevich, Y., Chowdhury, I., Pak, J.H., Kazi, A., Dodia, C., Speicher, D.W., and Fisher, A.B. (2009) Mitogen activated protein kinase-mediated phosphorylation of peroxiredoxin 6 regulates its phospholipase A2 activity. Biochem J. Jan. 14, 2009. Epub ahead of print. PMID: 19140803 Gaetani, M., Mootien, S, Harper, S, Gallagher, PG., and Speicher, D.W. (2008) Structural and functional effects of hereditary hemolytic anemia-associated point mutations in the alpha spectrin tetramer site. Blood 111:5712-5720. PMID: 18218854 Li, D., Tang, H.-Y, and Speicher, D.W. (2008) A structural model of the erythrocyte spectrin heterodimer initiation site determined using homology modeling and chemical crosslinking. J. Biol. Chem. 283:1553-1562. PMID: 17977835 Li, D., Harper, S. and Speicher, D.W. (2007) Initiation and propagation of spectrin heterodimer assembly involves distinct energetic processes. Biochemistry 46:10585-10594. PMID: 17713925 Johnson, C.P., Tang, H-Y., Carag, C., Speicher, D.W. and Discher, D.E. (2007) Forced unfolding of proteins within cells. Science 317:663-666. PMID: 17673662 Johnson, C.P., Gaetani, M., Ortiz, V., Bhasin, N., Harper, S., Gallagher, P.G.., Speicher, D.W. and Discher, D. (2007) Pathogenic proline mutation in linker between spectrin repeats: disease caused by spectrin unfolding. Blood 109:3538-3543. PMID: 17192394 Hoffman, S.A., Joo, W-A., Echan, L.A. and Speicher, D.W. (2007) Higher dimensional (Hi-D) separation strategies dramatically improve the potential for cancer biomarker detection in serum and plasma. Journal of Chromatography B 849:43-52. PMID: 17140865 Tang, H-Y., Ali-Khan, N., Echan, L.A., Levenkova, N., Rux, J.J. and Speicher, D.W. (2005) A novel 4-dimensional strategy combining protein and peptide separation methods enables detection of low abundance proteins for comprehensive profiling in human plasma and serum proteomics. Proteomics 5:3329-3342. PMID: 16052622 Tang, H.-Y., Speicher, D.W. (2004) In vivo phosphorylation of human erythrocyte spectrin occurs in a sequential manner. Biochemistry 43:4251-4262. |
