个人简介
I received my training as an analytical chemist at Purdue University, a leading institution in analytical chemistry, especially in the field of mass spectrometry. My career as an analytical chemist started in 2002 when I joined Dr. Fred Regnier’s group, a preeminent laboratory in separation and bio-mass spectrometry. There I conducted cutting edge research in the fields of chromatography and mass spectrometry. One of my main accomplishments as a graduate student was the development of chromatographic enrichment strategies for isolating carbonylated proteins from oxidatively stressed cells. Oxidative stress is caused by a set of free radicals known as reaction oxygen species (ROS) which are equally capable of modifying DNA, a condition underlying many types of cancer. There is also evidence indicating that the level of ROS is differentially regulated in cancer cells. Because of this fact, various forms of oxidatively modified proteins including carbonyated proteins have been targeted for cancer biomarker discovery.
In order to isolate low abundance carbonylated proteins from damaged cells, I developed a platform based on chemical tagging (biotin) and affinity chromatography (avidin). Isolated proteins were then characterized using a combination of advance chromatographic fractionation in conjunction with shotgun mass spectrometry.
In an attempt to make this platform high throughput, I developed a different labeling strategy that would allow the enrichment of carbonylated proteins using Strong Cation Exchange (SCX) chromatography. This type of chromatography is more robust and easier to use in tandem with high pressure Reversed-Phase Chromatography (RPC). This strategy provided an automated platform for analysis of carbonylated proteins with minimum sample handling. In addition, I used stable isotope labeling to accomplish relative quantification of carbonylated proteins, a capability which never existed before.
I have also made significant contributions to the field of mass spectrometry. One of the major limitations in mass spectrometry based biomarker discovery is the limit of detection. Most biomarkers are low abundance proteins that cannot be detected by common mass spectrometers. The limit of detection in mass spectrometry is determined by the ionization efficiency of the ion source used to ionize the peptides. I devised a labeling strategy that enhanced the ionization efficiency of the electrospray ionization method up to 500 fold.
In addition to developing novel analytical techniques, I have employed analytical techniques to tackle major biological questions. In 2006, we published a paper in the Journal of Proteome Research articulating a new theory explaining the cellular memory of aging. In this study, we used the power of analytical chemistry to identify hundreds of oxidatively modified proteins and their oxidation sites to describe how oxidative damage leads to an accumulation of specific modifications. we also discovered how oxidative modifications cause significant damage to ribosomal proteins and RNA, a condition that explains many irregularities caused by ROS in cells.
I also have been involved in targeted biomarker discovery efforts at Purdue. In a paper published in Proteomics in 2008, we showed how the enrichment strategies that I had developed as a graduate student at Purdue could be used to isolate and identify oxidized proteins, markedly increased in cancer, from rat plasma.
In late 2006 I joined Dr. Ruedi Aebersold’s laboratory at Institute for Systems Biology. This laboratory is one of the leading labs in proteomics research in the world. During my time there, I mainly focused on the development and application of new quantitative proteomics methods. In many biological processes, proteins that are expressed at low levels are key components of the system, so accurate detection and quantification of low abundance proteins is crucial for systems biology and personalized medicine research. Success in detecting and quantifying low abundance proteins is often limited when common proteomics approaches such as shotgun mass spectrometry are used. These shortcomings mainly stem from the limitations of the shotgun platform in resolving the contents of biological samples and from the inefficient use of ions in mass spectrometry.
During my postdoctoral research at ISB, I was involved in the development of Selected Reaction Monitoring (SRM), a newly adopted mass spectrometry technique that promises to revolutionize proteomics into an automated, accurate and reproducible data acquisition platform. This technology does not require the often limiting step of precursor ion selection for peptide ion fragmentation, but instead uses mass analyzers to monitor predefined peptide and fragment ion pairs.
I was involved in the development of the first complete SRM library for an organism (S. cerevisiae) published in Nature Methods in 2008 and employed SRM assays for the detection and quantification of the entire set of transcription factors in S. cerevisiae. This work was the first to show that these assays are selective enough to detect target transcription factors directly from yeast nuclear extract and sensitive enough to detect these factors in minute samples of proteins bound to segments of DNA.
I also applied SRM technology towards quantitative analysis of post-translational modifications of proteins. Post-translational modifications modulate the activity of most eukaryote proteins. Detection and quantification of post-translational modifications has always been challenging for reasons such as low abundance, structural diversity, and chemical and biological instability. Ubiquitination is a significant cell-signaling mechanism with diverse structural forms. Even though polyubiquitinated proteins can be purified, mapping the topography of such moieties necessary for elucidation of their function is extremely challenging due to the heterogeneous distribution of linkages between the lysines of ubiquitin. I developed a comprehensive targeted mass spectrometry assay (SRM) sensitive enough to measure the frequency and density of intraubiquitin linkages at the single protein level and specific enough to detect them in complex mixtures such as whole cell lysate. I used this assay to determine the frequency of different intraubiquitin linkages in polyubiquitinated proteins enriched from yeast as well as changes in linkage frequency at the single protein level and whole lysate level after cells were treated with toxins such as methyl methanesulfonate and cadmium.
I have also contributed significantly in areas of platform standardization, reproducibility and transferability in proteomics. We published two papers in Molecular & Cellular Proteomics in 2008 and 2009 describing new strategies to make mass spectrometry more reproducible and transferable. A patent is pending based on this work. I also was part of the panel that set the guidelines for reporting the use of column chromatography in proteomics published in Nature Biotechnology in 2010.
Education
Undergraduate Isfahan University - Iran (1999), Chemistry
Graduate School Ball State University (2001), Chemistry
Graduate School Purdue University Main Campus (2005), ChemistryHonors & Awards
Missing Links Award
Cancer Prevention Research Institute of Texas (2011)
Top 10 most cited author of the year
ACS (2006)
Deans Citation for Academic Excellence
Ball State University (2001)
Outstanding Chemistry Graduate Student and Graduate Teaching Award
Ball State University (2001)
近期论文
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P7C3 Neuroprotective Chemicals Function by Activating the Rate-Limiting Enzyme in NAD Salvage.
Gelin Wang, Ting Han, Deepak Nijhawan, Pano Theodoropoulos, Jacinth Naidoo, Sivaramakrishnan Yadavalli, Hamid Mirzaei, Andrew A. Pieper, Joseph M. Ready & Steven L. McKnight. Cell, 158(6), 1324-34, 2014
Marker for type VI secretion system effectors.
Salomon D, Kinch LN, Trudgian DC, Guo X, Klimko JA, Grishin NV, Mirzaei H, Orth K.Proc. Natl. Acad. Sci. U.S.A. 2014 Jun
GOAT - A simple LC-MS/MS gradient optimization tool.
Trudgian DC*, Fischer R*, Guo X, Kessler BM, Mirzaei H. PROTEOMICS 2014 Apr
Confetti: A Multi-protease Map of the HeLa Proteome for Comprehensive Proteomics.
Guo X*, Trudgian DC*, Lemoff A, Yadavalli S, Mirzaei H. Mol. Cell Proteomics 2014 Apr
Phosphorylation-regulated binding of RNA polymerase II to fibrous polymers of low-complexity domains.
Kwon I, Kato M, Xiang S, Wu L, Theodoropoulos P, Mirzaei H, Han T, Xie S, Corden JL, & McKnight SL. Cell, 155(5), 1049-60, 2013
Regulation of OSR1 and the sodium, potassium, two chloride cotransporter by convergent signals.
Sengupta S, Lorente-Rodriguez A, Earnest S, Stippec S, Guo X, Trudgian DC, Mirzaei H, Cobb MH Proc. Natl. Acad. Sci. U.S.A. 2013 Nov
A gain-of-function mutation in DHT synthesis in castration-resistant prostate cancer
Chang KH, Li R, Kuri B, Lotan Y, Roehrborn CG, Liu J, Vessella R, Nelson PS, Kapur P, Guo X, Mirzaei H, Auchus RJ & Sharifi N., Cell, 154(5), 1074-84, 2013
Sulfur Amino Acids Regulate Translational Capacity and Metabolic Homeostasis through Modulation of tRNA Thiolation.
Laxman, S., Sutter, B. M., Wu, X., Kumar, S., Guo, X., Trudgian, D. C., Mirzaei, H. & Tu, B. P., Cell, 154(2), 416-429, 2013.
Systematic measurement of transcription factor-DNA interactions by targeted mass spectrometry identifies candidate gene regulatory proteins.
H. Mirzaei, T. A. Knijnenburg, B. Kim, M. Robinson, P. Picotti, G. W. Carter, S. Li, D. J. Dilworth, J. K. Eng, J. D. Aitchison, I. Shmulevich, T. Galitski, R. Aebersold and J. Ranish, PNAS, Early Edition doi: 10.1073/pnas.1216918110, 2013.
Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1.
Sun Q, Carrasco YP, Hu Y, Guo X, Mirzaei H, Macmillan J, & Chook YM, Proc Natl Acad Sci USA,110(4), 1303-8, 2013.
Cloud CPFP: A Shotgun Proteomics Data Analysis Pipeline Using Cloud and High Performance Computing.
Trudgian DC, Mirzaei H, Journal of proteome research, 2012 Oct;
Type III Effector VopC Mediates Invasion for Vibrio Species.
Zhang, L., Krachler, A. M., Broberg, C. A., Li, Y., Mirzaei, H., Gilpin, C. J., & Orth, K., Cell reports, 1(5), 453-460, 2012.
Cell-Free formation of RNA granules: bound RNAs identify features and components of cellular assemblies.
Han TW, Kato M, Xie S, Wu LC, Mirzaei H, Pei J, Chen M, Xie Y, Allen J, Xiao G, McKnight SL, Cell, 149(4):768-79, 2012
Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels.
Kato M, Han TW, Xie S, Shi K, Du X, Wu LC, Mirzaei H, Goldsmith EJ, Longgood J, Pei J, Grishin NV, Frantz DE, Schneider JW, Chen S, Li L, Sawaya MR, Eisenberg D, Tycko R, McKnight SL, Cell, 149(4):753-67, 2012.
Glutathione-S-transferase P1 is a critical regulator of Cdk5 kinase activity.
Sun KH, Chang KH, Clawson S, Ghosh S, Mirzaei H, Regnier F, Shah K, Journal of neurochemistry, 2011 Sep 5 (118) 1471-4159
Characterizing the connectivity of poly-ubiquitin chains by selected reaction monitoring mass spectrometry.
Mirzaei H, Rogers RS, Grimes B, Eng J, Aderem A, Aebersold R, Molecular bioSystems, 2010 Oct 10 (6) 1742-2051
QTIPS: a novel method of unsupervised determination of isotopic amino acid distribution in SILAC experiments.
Dilworth DJ, Saleem RA, Rogers RS, Mirzaei H, Boyle J, Aitchison JD, Journal of the American Society for Mass Spectrometry, 2010 Aug 8 (21) 1879-1123
Guidelines for reporting the use of column chromatography in proteomics.
Jones AR, Carroll K, Knight D, Maclellan K, Domann PJ, Legido-Quigley C, Huang L, Smallshaw L, Mirzaei H, Shofstahl J, Paton NW, Nature biotechnology, 2010 Jul 7 (28) 1546-1696
Synthesis, metabolism and in vitro cytotoxicity studies on novel lavendamycin antitumor agents.
Cai W, Hassani M, Karki R, Walter ED, Koelsch KH, Seradj H, Lineswala JP, Mirzaei H, York JS, Olang F, Sedighi M, Lucas JS, Eads TJ, Rose AS, Charkhzarrin S, Hermann NG, Beall HD, Behforouz M, Bioorganic & medicinal chemistry, 2010 Mar 5 (18) 1464-3391
Proteins That Underlie Neoplastic Progression of Ulcerative Colitis.
Brentnall TA, Pan S, Bronner MP, Crispin DA, Mirzaei H, Cooke K, Tamura Y, Nikolskaya T, Jebailey L, Goodlett DR, McIntosh M, Aebersold R, Rabinovitch PS, Chen R, Proteomics. Clinical applications, 2009 Sep 11 (3) 1862-8354
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