Ian A. Blair
University of Pennsylvania School of Medicine
Center for Cancer Pharmacology
421 Curie Boulevard
Philadelphia, PA 19104-6160
Fax: (215) 573-9889
Cambridge Grammar School for Boys, United Kingdom , 1960.
Prince of Wales School, Nairobi, Kenya, 1963.
B.Sc. ((Special) Chemistry, ARCS)
Imperial College of Science and Technology, University of London, United Kingdom, 1968.
Imperial College of Science and Technology, University of London, United Kingdom, 1971.
MRSC (Organic Chemistry)
Adelaide University, Australia, 1972.
Australian National University, 1977.
Description of Research ExpertiseEstablish the use of high-resolution mass spectrometry and molecular biology as tools for conducting sophisticated proteomics, DNA-adductomics, metabolomics, and lipidomics research with a particular emphasis on discovering biomarkers for the early detection of cancer and biomarkers of response in rare diseases
1. Early detection biomarkers of asbestos exposure, mesothelioma, and non-small lung cancer,
Amyloid β-peptides and high-mobility group box 1 (HMGB1) a non-histone chromosomal protein are the two most intensively studied endogenous cellular danger signals known as danger-associated molecular pattern (DAMP) molecules. DAMPs together with pathogen-associated molecular patterns alert the innate immune system by activating signal transduction pathways through binding to pattern recognition receptors (PRRs). PRRs include the receptor for advanced glycation end products (RAGE), toll-like receptors (TLRs), chemokine (C-X-C motif) receptor (CXCR), and T cell immunoglobulin mucin (TIM). Binding to PRRs induces pro-inflammatory cascades, which trigger the release of cytokines. PRRs are expressed by cells of the innate immune system such as macrophages, leukocytes and dendritic cells. They are also expressed on the surface of vascular cells, fibroblasts and epithelial cells. We have recently demonstrated that HMGB1 is secreted when blood is allowed to clot. Numerous studies have reported that HMGB1 is secreted in o the circulation by cancer patients. However, many of these studies are flawed because they used serum instead of plasma. Furthermore there are 29 reported sites of acetylation on HMGB1 so it is essential that the methodology is available to quantify each of the individual proteoforms. We are currently developing an approach for the analysis of HMGB1 proteoforms in plasma samples from patients with mesothelioma and non-small cell lung cancer as well as subjects who had a heavy exposure to asbestos. We are also quantifying lipid hydroperoxide-mediated DNA damage in lymphocytes from the same population in order to further understand the etiology of the disease. Finally, metabolomics and lipidomics studies are being conducted in order to discover additional biomarkers.
2. Biomarkers of therapeutic response in rare diseases.
There are > 40 rare genetic diseases that result from aberrant protein expression including, Duchene’s muscular dystrophy (DMD), spinocerebellar ataxia 1 (SCA-1), and Friedreich’s ataxia (FA). Current approaches to developing therapies for these rare diseases primarily involve increasing expression of the normal protein. The necessity for monitoring protein levels was highlighted recently during the US Food and Drug Administration (FDA) fast-track approval process for the drug eteplirsen (Exondys 51) to treat DMD. The lack of a rigorously validated method to assess up-regulation of dystrophin levels in DMD patients made it difficult to show a therapeutic response. FA is characterized by slowly progressive ataxia and hypertrophic cardiomyopathy. Lifespan is significantly reduced in FA with an average of death of 37-years, most commonly from cardiac-related pathologies. There are no approved treatments for FA, although numerous experimental approaches are being tested, which primarily involve up-regulation of frataxin protein. We have developed a strategy to monitor improvements in mitochondrial metabolism using FA platelets. We are now developing more direct measure of frataxin expression. This will also provide an approach to monitor new therapies that are being developed for rare genetic diseases of aberrant protein expression such as DMD24 and SCA-1.
Description of Itmat ExpertiseDr. Blair is interested in oxidative stress in cancer, cardiovascular disease, and neurodegenerative disease including the investigation of the role of endogenous DNA- and glutathione-adducts as biomarkers of cancer and cardiovascular disease in vitro, in animal models and humans. He is also developing metabolomic biomarkers of neurodegenerative diseases in humans and in animal models.
Selected PublicationsWeng L, Guo L, Vachani A, Mesaros CA, Blair IA: Quantification of Serum High Mobility Group Box-1 by Liquid Chromatography High Resolution Mass Spectrometry: Implications for its role in Immunity, Inflammation, and Cancer. Anal Chem May 2018.
Ecker C, Guo L, Voicu S, Gil-de-Gómez L, Medvec A, Cortina L, Pajda J, Andolina M, Torres-Castillo M, Donato JL, Mansour S, Zynda ER, Lin PY, Varela-Rohena A, Blair IA, Riley JL: Differential Reliance on Lipid Metabolism as a Salvage Pathway Underlies Functional Differences of T Cell Subsets in Poor Nutrient Environments. Cell Rep 23(3): 741-755, APR 2018.
Friedman ES, Bittinger K, Esipova TV, Hou L, Chau L, Jiang J, Mesaros C, Lund PJ, Liang X, FitzGerald GA, Goulian M, Lee D, Garcia BA, Blair IA, Vinogradov SA, Wu GD: Microbes vs. chemistry in the origin of the anaerobic gut lumen. Proc Natl Acad Sci USA 115(16): 4170-4175, Apr 2018.
O'Connor RS, Guo L, Ghassemi S, Snyder NW, Worth AJ, Weng L, Kam Y, Philipson B, Trefely S, Nunez-Cruz S, Blair IA, June CH, Milone MC: The CPT1a inhibitor, etomoxir induces severe oxidative stress at commonly used concentrations. Sci Rep 8(1): 6289, Apr 2018.
Shrimp JH, Garlick JM, Tezil T, Sorum AW, Worth AJ, Blair IA, Verdin E, Snyder NW, Meier JL.: Defining Metabolic and Nonmetabolic Regulation of Histone Acetylation by NSAID Chemotypes. Mol Pharm. 15(3): 729-736, Mar 2018.
Mazaleuskaya LL, Salamatipour A, Sarantopoulou D, Weng L, FitzGerald GA, Blair IA, Mesaros C. : Analysis of hydroxyeicosatetraenoic acids (HETEs) in human whole blood by chiral ultrahigh performance liquid chromatgraphy (UHPLC)-electron capture atmospheric pressure chemical ionization/high resolution mass spectrometry (ECAPCI/HRMS). J Lipid Res. 59(3): 564-575, Mar 2018.
Yue W, Wang J, Atkins KA, Bottalico L, Mesaros C, Blair IA, Santen RJ: Effect of a tissue selective estrogen complex (TSEC) on breast cancer: Role of unique properties of conjugated equine estrogen. Int J Cancer Mar 2018 Notes: doi: 10.1002/ijc.31401. [Epub ahead of print]
Guo L, Wang Q, Weng L, Hauser LA, Strawser CJ, Rocha AG, Dancis A, Mesaros C, Lynch DR, Blair IA. : Liquid Chromatography-High Resolution Mass Spectrometry Analysis of Platelet Frataxin as a Protein Biomarker for the Rare Disease Friedreich's Ataxia. Anal Chem. 90(3): 2216-2223, Feb 2018.
Wang Q, Guo L, Strawser CJ, Hauser LA, Hwang WT, Snyder NW, Lynch DR, Mesaros C, Blair IA : Low apolipoprotein A-I levels in Friedreich's ataxia and in frataxin-deficient cells: Implications for therapy. PLoS One 13(2): e0192779, Feb 2018.
Huang M, Mesaros C, Hackfeld LC, Hodge RP, Blair IA, Penning TM.: Potential Metabolic Activation of Representative Alkylated Polycyclic Aromatic Hydrocarbons 1-Methylphenanthrene and 9-Ethylphenanthrene Associated with the Deepwater Horizon Oil Spill in Human Hepatoma (HepG2) Cells. Chem Res Toxicol. 30(12): 2140-2150, Dec 2017.