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Blair Lab Bio

Dr. Ian Blair

Blair

A. N. Richards Professor of Pharmacology

Vice-Chair, Department of Pharmacology

Director, Center for Cancer Pharmacology

Director, Proteomics and Systems Biology Facility

Director, Molecular Profiling Core, Center of Excellence in Environmental Toxicology

Education:
1968 BSc (Chemistry) University of London
1968 ARCS Royal College of Science
1971 DIC Imperial College of Science and Technology
1971 Ph.D. (Organic Chemistry) University of London (Advisor, Nobel Laureate Sir Derek HR Barton)
1997 MA (Honorary) University of Pennsylvania

Research Summary:
Research in the Blair laboratory is heavily involved in the use of mass spectrometry for proteomics and DNA analysis.

Oxidative stress, carcinogenesis, and cardiovascular disease

The reactive oxygen species superoxide, peroxide, and hydroxyl radical, are generated constantly in vivo from ground state triplet oxygen. This occurs by a variety of endogenous processes including, normal mitochondrial aerobic respiration, phagocytosis of bacteria or virus-containing cells, and peroxisomal-mediated degradation of fatty acids. Catechols, which arise in vivo through the metabolism of drugs, environmental chemicals, and endogenous hormones, generate reactive oxygen species through redox cycling. The reactive oxygen species are normally detoxified by antioxidant defense systems such as, superoxide dismutase, catalase, reduced glutathione (GSH)-dependent peroxidases, and thioredoxin. Some of the reactive oxygen species are able to escape these defenses in order to perform important metabolic roles.

This means that there is always a potential for damage to lipids and macromolecules such as proteins, peptides, and DNA, particularly in settings of oxidative stress. Lipid damage involves the formation of lipid hydroperoxides, which undergo homolytic decomposition to the aldehydic genotoxins, 4-oxo-2-nonenal, 4,5-epoxy-2(E)-decenal, and 4-hydroxy-2-nonenal through two quite distinct pathways. We have shown that one pathway involves a complex rearrangement of the alkoxy radical derived from the lipid hydroperoxide and the other pathway involves the intermediate formation of another potential genotoxin, 4-hydroperoxy-2-nonenal. Lipid hydroperoxides can also be derived from the action of lipoxygenases and cyclooxygenases on polyunsaturated fatty acids. 4,5-Epoxy-2(E)-decenal forms the unsubstituted etheno-2-deoxyadenosine adduct with DNA, a mutagenic lesion which as been observed in human tissue DNA samples. Several new ethano- and etheno-DNA-adducts have been identified from the reaction of 4-oxo-2-nonenal with DNA. However, nothing is known about how these lesions affect proliferation or apoptosis. A role for 4-oxo-2-nonenal in the covalent modifications of proteins is also possible. 4-Hydroxy-2-nonenal forms propano adducts with 2'-deoxyguansine and also up-regulates cyclooxygenase-2 expression. As cyclooxygenase-2 converts arachidonic acid into lipid hydroperoxides, this provides a potential mechanism for increased production of genotoxic bifunctional electrophiles. Our laboratory is involved in determining the factors that control oxidative stress-mediated damage to proteins, peptides and DNA. We are quantifying these modified proteins, peptides, and DNA together with selected endogenous metabolites using novel mass spectrometry methodology to act as biomarkers for assessing whether such processes occur in cardiovascular disease and cancer. We are also determining whether their formation can be prevented using novel pharmacological agents.

Key References:

2011

Rangiah K, Hwang WT, Mesaros AC, Vachani A, and Blair IA. (2011) Nicotine exposure and metabolizer phenotypes from analysis of urinary nicotine and its fifteen metabolites by liquid chromatography-mass spectrometry. Bioanalysis 3(7):745-61.

Mitra R, Guo Z, Milani M, Mesaros C, Rodriguez M, Nguyen J, Luo X, Clarke D, Lamba J, Schuetz E, Donner DB, Puli N, Falck JR, Capdevila J, Gupta K, Blair IA, Potter DA . (2011) CYP3A4 mediates growth of ER+ breast cancer cells, in part, by nuclear translocation of phospho-Stat3 through biosynthesis of ({+/-})-14,15-EET. J. Biol Chem [Epub ahead of print Mar 14]

Basu SS, Mesaros C, Gelhaus SL, Blair IA. (2011) Stable Isotope Labeling by Essential Nutrients in Cell Culture (SILEC) for the Preparation of Labeled Coenzyme A Thioesters. Anal Chem. 83(4):1363-9. PMCID: PMC3048769

Mitra R, Lee J, Jo J, Milani M, McClintick JN, Edenberg HJ, Kesler KA, Rieger KM, Badve S, Cummings OW, Mohiuddin A, Thomas DG, Luo X, Juliar BE, Li L, Mesaros C, Blair IA, Srirangam A, Kratzke R, McDonald CJ, Kim J, Potter DA. (2011) Prediction of Postoperative Recurrence-Free Survival in Non-small Cell Lung Cancer by Using an Internationally Validated Gene Expression Model. Clin Cancer Res. 2011 Jan 17. [Epub ahead of print]

Bhat SH, Gelhaus SL, Mesaros AC, Vachani A, Blair IA. (2011) A new liquid chromatography/ mass spectrometry method for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in urine. Rapid Commun Mass Spectrom 25, 115–121. PMCID Journal in Progress

Gelhaus SL, Harvey RG, Penning TM and Blair IA. (2011) Regulation of Benzo[a]pyrene-Mediated DNA-and Glutathione-Adduct Formation by 2,3,7,8-Tetrachlorodibenzo-p-dioxin in Human Lung Cells. Chem Res Toxicol. 24(1):89-98. PMCID: PMC3021323.

Fong KP, Barry C, Tran AN, Traxler EA, Wannemacher KM, Tang HY, Speicher KD, Blair IA, Speicher DW, Grosser T, Brass LF. (2011) Deciphering the human platelet sheddome. Blood. 117(1):e15-26. PMCID: PMC3037762 [Available on 2012/1/6]

2010

Byrns MC, Duan L. Lee SH, Blair IA, Penning TM. (2010) Aldo-keto reductase 1C3 expression in MCF-7 cells reveals roles in steroid hormone and prostaglandin metabolism that may explain its over-expression in breast cancer. J. Steroid Biochem Mol Biol 118(3): 177-187. PMCID: PMC2819162

Ciccimaro E, and Blair, IA. (2010) Stable isotope-dilution LC–MS for quantitative biomarker analysis. Bioanalysis. 2(2), 311–341. PMCID: PMC2843934

Cooper PR, Mesaros AC, Zhang J, Christmas P, Stark CM, Douaidy K, Mittelman MA, Soberman RJ, Blair IA, Panettieri, Jr. RA. (2010) 20-HETE mediates ozone-induced, neutrophil-independent airway hyper-responsiveness in mice. PLoS ONE 5(4):e10235. PMCID: PMC2857875

Mesaros C, Lee SH, Blair IA. (2010) Analysis of epoxyeicosatrienoic acids by chiral liquid chromatography/electron capture atmospheric pressure chemical ionization mass spectrometry using [(13)C]-analog internal standards. Rapid Commun. Mass Spectrom 24(22):3237-47. PMCID Journal in Progress

Blair, IA. (2010) Analysis of Estrogens in Serum and Plasma from Postmenopausal Women: Past Present, and Future. Steroids 75(4-5): 297-306. PMCID: PMC2840185 [Available on 2011/4/1]

Blair, I.A. (2010) Analysis of endogenous glutathione-adducts and their metabolites. Biomed Chromatogr 24:29-38.

2009

  • Savitski AN, Mesaros C, Blair IA, Cohen NA, Kreindler JL. (2009) Secondhand smoke inhibits both Cl- and K+ conductances in normal human bronchial epithelial cells. Respir Res 10(1):120. PMCID: PMC2792224.
  • Rangiah K, Tippornwong M, Sangar V, Austin D, Tétreault M-P, Rustgi AK., Blair IA, Yu KH. (2009) Differential secreted proteome approach in murine model for candidate biomarker discovery in colon cancer. J. Proteome Res. 8(11):5153-64 . PMCID: PMC2783939 [Available on 2010/11/1].
  • Lee SH, Blair IA. Targeted chiral lipidomics analysis of bioactive eicosanoid lipids in cellular systems. BMB Rep 42(7):401-410. PMID19643036 - Free Article
  • Wei C, Zhu P, Shah SJ, Blair IA. 15-Oxo-Eicosatetraenoic Acid, a Metabolite of Macrophage 15-Hydroxyprostaglandin Dehydrogenase that Inhibits Endothelial Cell Proliferation. Mol Pharmacol 76(3):516-25. PMCID: PMC2730384 [Available on 2010/09/01].
  • Jian W, Lee SH, Williams MV, Blair IA. (2009) 5-Lipoxygenase-mediated Endogenous DNA Damage. J Biol Chem 284(25):16799-807. PMCID: PMC 2719316
  • Mesaros, C., Lee, S. H., and Blair, I. A. (2009) Targeted quantitative analysis of eicosanoid lipids in biological samples using liquid chromatography-tandem mass spectrometry. J. Chromatogr. B 877(26):2736-45. PMCID: PMC2745066 [Available on 2010/09/15].
  • Yu, KH, Barry CG, Austin D, Busch C.M, Sangar V, Rustgi A.K, Blair I.A. Stable isotope dilution multidimensional liquid chromatography-tandem mass spectrometry for pancreatic cancer serum biomarker discovery. J Proteome Res 8(3):1565-1576. PMCID: PMC2652408

2008

Blair, IA. DNA-adducts with lipid peroxidation products. J Biol Chem. 2008 283(23):15545-9. PMID: 18285329.

Lucitt MB, Price TS, Pizarro A, Wu W, Yocum AK, Seiler C, Pack MA, Blair IA, Fitzgerald GA, Grosser T. (2008) Analysis of the zebrafish proteome during embryonic development. Mol Cell Proteomics. 7(5):981-94. PMCID: PMC2401336

2005

Yocum, A.K., Yu, K.H., Oe, T., Blair, I.A. (2005) “Effect of immunoaffinity depletion of human serum during proteomic investigations.” J. Proteome Res. 4: 1722-31.

Yu KH, Rustgi AK, Blair IA. (2005) Characterization of proteins in human pancreatic cancer serum using differential gel electrophoresis and tandem mass spectrometry. J. Proteome Res. 4: 1742-1751.

2001

Lee, S.H., Oe, T. and Blair, I.A. (2001) “Vitamin C-induced decomposition of lipid hydroperoxides to endogenous genotoxins.” Science 292:(5524) 2083-2086.

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