UW-Madison School of Pharmacy

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Lingjun Li, PhD

Professor
Janis Apinis Prof. of PharmSci.; Vilas Distinguished Achievement Prof.

 

 

 


Research in my laboratory focuses on developing and implementing an array of novel mass spectrometry based strategies to answer questions about the most complex and elusive set of signaling molecules, the neuropeptides, and gain new insights into the roles of peptide hormones and neurotransmitters play in the plasticity of neural circuits and behavior. While significant effort has been directed to analytical technique and method development, it is the biomedical importance of understanding the neuropeptidergic system that drives our research to continuously refine and improve the analytical capabilities to address challenging neuroscience problems. A large body of research strongly suggests that an imbalance of chemical messengers is associated with various neurological disorders. However, compared to classical neurotransmitters such as amines, the functional roles of many neuropeptides are still poorly understood. This is, in part, due to the lack of analytical capabilities to measure and identify these low abundance endogenous signaling molecules in a complex microenvironment. Clearly, development of highly sensitive and selective analytical tools for neuropeptide identification and quantitation is in great demand. Specifically, we are interested in understanding the roles that neuropeptides play in food intake, neural network development and response to environmental stresses.

We have chosen to work with a simpler and well-defined crustacean nervous system to both facilitate technology development and address fundamental neuroscience problems related to neuromodulation and network plasticity. We are developing a multi-faceted mass spectrometry-based analytical platform to probe peptidergic signaling with enhanced sensitivity and selectivity. By combining chemical labeling, micro-scale separation (capillary electrophoresis and nanoLC), and tandem mass spectrometry sequencing techniques, we have discovered a large number of novel neuropeptides in crustacean nervous systems. The physiological effects of these new peptides at the cellular and network levels are evaluated in collaboration with neurophysiologists (Eve Marder and Michael Nusbaum) in the field. Furthermore, both mass spectrometric imaging technology and in vivo microdialysis sampling tools have been implemented to follow neuropeptide distribution and secretion with unprecedented details. Finally, a differential display strategy in conjunction with isotopic labeling technique is being developed to allow functional discovery of neuropeptides in response to various physiological changes.

While the technology is developed using crustacean model system as a test-bed, the technology advancement resulting from our research is widely applicable to the large-scale analysis of peptides and proteins in many biological systems, including those of mammalian and humans. Towards this end, we have established several exciting collaborations targeted at neurochemical analysis in more complex systems. These collaborative projects include biomarker discovery in neurodegenerative diseases (with Albee Messing and Judd Aiken), peptide analysis and neuromodulation in mammalian rhythmic neural network (with Jan Marino (Nino) Ramirez), proteomic analysis neuroprotective factors secreted by astrocytes (with Jeffrey Johnson), and proteomic study of dioxin-induced cardiotoxicity in developing zebrafish (with Warren Heideman and Richard Peterson).

These synergistic projects span analytical mass spectrometry, capillary separations, peptide chemistry, bioinformatics, neurochemistry, and neurobiology. The improved analytical method development enables biological discovery, and the emerging biological questions require further advancement of analytical tools.

Li Lab Research Overview

Background: Lingjun received her BE degree in Environmental Analytical Chemistry from Beijing Polytechnic University and a PhD degree in Analytical Chemistry/Biomolecular Chemistry from University of Illinois at Urbana-Champaign. She did three-way postdoctoral research at the Pacific Northwest National Laboratory, Brandeis University, and University of Illinois before joining the School of Pharmacy faculty in 2002. She currently holds joint appointments in School of Pharmacy and Department of Chemistry at UW-Madison. Her research interests are in analytical neurochemistry, neuroproteomics and biological mass spectrometry.

Professional Interests: Drug Action and Drug Discovery

Education:

  • BE 1992 Env. Analyt. Chem. - Beijing Polytechnic University
  • PhD 2000 Analyt & Biomol Chem - University of Illinois at Urbana-Champaign (UIUC)
  • Postdoc 2002 Analyt Chem/NeuroSci - Pacific Northwest National Laboratory, Brandeis University, UIUC
Highlighted Publications:
  • A. Buchberger, Q. Yu, and L. Li* (2015).  Advanced in mass spectrometric tools for probing neuropeptides.  Annual Review of Analytical Chemistry, 8, invited contribution.  In press.
  • H.C. Cohen, D.C. Frost, T.J. Lieberthal, L. Li, and W.J. Kao* (2015).  Biomaterials differentially regulate Src fkinases and phosphoinositide 3-kinase-gamma in polymorphonuclear leukocyte primary and tertiary granule release.  Biomaterials, 50, 47-55.
  • X. Zhong, Z. Chen, S. Snovida, Y. Liu, J.C. Rogers, and L. Li* (2015).  Capitllary electrophoresis-electrospray ionization-mass spectrometry analysis of glycans using multiplexed carbonyl-reactive tandem mass tags.  Analytical Chemistry.  In press.
  • T. Greer, A. Nechyporenko, L. Hao, D. Frost, C. Vezina, W. Ricke, P. Marker, D. Bjorling, W. Bushman, and L. Li* (2014).  Identification and comparison of protein candidate biomarkers from lower urinary tract symptoms (LUTS) in human patients.  PLOS ONE.  Under revision.
  • D. Frost, T. Greer, F. Xiang, Z. Liang, and L. Li* (2015).  Development and characterization of novel 8-plex DiLeu isobaric labels for quantitative proteomics and peptidomics.  Rapid Communication in Mass Spectrometry.  29, 1115-1124.  doi:  10.1002/rcm.7201
  • E. Gemperline, D. Jayaraman, J. Maeda, J-M. Ane, and L. Li* (2015).  Multifaceted investigation of metabolites during nitrogen fixation in Medicago via high resolution MALDI-MS imaging and ESI-MS.  Journal of American Society for Mass Spectrometry.  26, 149-158.  DOI:  10.1007/s13361-014-1010-0.
  • E. Pedroso-Silva, D. Frost, L. Li, N. Bovin, and D. Miller* (2015).  Identification of lactadherin as a Lewis X trisaccharide binding protein in porcine sperm.  Under revision.
  • Z. Liang, C. Schmerberg, and L. Li* (2015).  Mass spectrometric measurement of circadian rhythm related neuropeptides release in the crab, Cancer borealis, using in vivo microdialysis.  Analyst.  140, 3803-3813.  Invited contribution to a Themed Issue on In Vivo Analysis.  DOI:  10.1039/c4an02016b, http://pubs.rsc.org/en/content/articlepdf/2014/an/c4an02016b
  • T. Greer, C.B. Lietz, F. Xiang, and L. Li* (2015).  Novel isotopic N,N-dimethyl leucine (iDiLeu) reagents enable absolute quantification of peptides and proteins using a standard curve approach.  Journal of American Society for Mass Spectrometry. 26, 107-119, http://dx.doi.org/10.1007/s13361-014-1012-y
  • L. Hao, X. Zhong, T. Greer, H. Ye, and L. Li* (2014).  Relative quantification of amine-containing metabolites using isobaric N,N-dimethyl-leucine (DiLeu) reagents via LC-ESI-MS/MS and CE-ESI-MS/MS. Analyst. 140, 467-475, DOI: 10.1039/c4an01582g. Selected as HOT article and featured on Analyst blog.
  • C. Ouyang, Z. Liang, and L. Li*(2014).  Mass spectrometric analysis of spatio-temporal dynamics of crustacean neuropeptides.  Biochim Biophys Acta (BBA)-Proteins and Proteomics.  Invited contribution to Special Issue on Neuroproteomics.  In press, 2014 Nov 4.  pii: S1570-9639(14)00291-X. DOI:10.1016/j.bbapap.2014.10.023. http:///www.sciencedirect.com/science/article/pii/S157096391400291X
  • R. Chen, M. Xiao, A. Buchberger, and L. Li* (2014).  Quantitative neuropeptidomics study of the effects of temperature change in the crab Cancer borealis.  Journal of Proteome Research.  13, 5767-5776.  Web publication date: September 12, 2014, DOI: 10.1021/pr500742q
  • K.P. Keil, L.L. Abler, H.M. Altmann, W. Bushman, P.C. Marker, L. Li, W.A. Ricke, D.E. Bjorling, and C.M. Vezina* (2014).  Influence of animal husbandry practices on void spot assay outcomes in C57BL/6J male mice.  Neurology and Urodynamics.  doi: 10.1002/nau.22692.
  • S. Jiang, Z. Zhang, and L. Li* (2015).  A one-step preparation method of monolithic enzyme reactor for highly efficient sample preparation coupled to mass spectrometry-based proteomics studies.  Journal of Proteomics.  To be submitted.
  • C. Yang, X. Zhong, and L. Li* (2014).  Recent advances in enrichment and separation strategies for mass spectrometry-based phosphoproteomics.  Electrophoresis Invited review for Special issue of Phosphoproteomics.  35, 3418-3429.  Published online March 29, 2014, doi: 10.1002/elps.201400017.
  • E. Gemperline and L. Li* (2014).  MALDI-mass spectrometric imaging of endogenous metabolites in biological systems.  Invited contribution to eLS (Encyclopedia of Life Sciences), John Wiley & Sons Ltd, Chichester, http://www.els.net [doi: 10.1002/9780470015902.a0023207]
  • R. Chen, C. Ouyang, M. Xiao, and L. Li* (2014).  In situ identification and mapping of neuropeptides from the stomatogastric nervous system of Cancer borealis.  Rapid Communication in Mass Spectrometry, 28, 2437-2444, DOI: 10.1002/rcm.7037.
  • E. Gemperline, K. Laha, C.O. Scarlett, R.A. Pearce, and L. Li* (2014).  Measurement of NMDA receptor antagonist, CPP, in mouse plasma and brain tissue following systematic administration using ion-pair LC-MS/MS.  Analytical Methods, 6, 6389-6396.
  • B. Chen, C.B. Lietz, and L. Li* (2014).  In situ characterization of proteins using laserspray ionization on a high-performance MALDI-LTQ-Orbitrap mass spectrometer.  Journal of American Society for Mass Spectrometry25, 2177-2180, Online published October 2, DOI: 10.1007/s13361-014-0986-9.
  • D. Frost, T. Greer, and L. Li* (2014).  High resolution enabled 12-plex isobaric tags for quantitative proteomics.  Analytical Chemistry.  In press.  DOI: 10.1021/ac503276z, Web publication on November 18.  http://pubs.acs.org/doi/abs/10.1021/ac503276zFeatured on the journal cover for February 3 issue and highlighted on ACS Podcast.
  • C. Lietz, Q. Yu, and L. Li*(2014).  Global peptide collision cross-section profiling on a travelling wave ion mobility mass spectrometer.  Invited contribution to a special focus issue of JASMS honoring Dr. Richard D. Smith, recipient of the 2013 Distinguished Contribution in Mass Spectrometry Award.  Journal of American Society for Mass Spectrometry25, 2009-2019, DOI: 10.1007/s13361-014-0920-1.
  • K. Katsumura, C. Yang, M. Boyer, L. Li, and E. Bresnick* (2014).  Leukemogenic GATA factor mutant reveals a hierarchical phosphorylation mechanism to control hematopoiesis.  EMBO Reports. 15, 938-47.  doi: 10.15252/embr.201438808. Epub 2014 Jul 23.  Featured as Hot Off the Press article in the journal.
  • C. Jia, Q. Yu, J. Wang, and L. Li* (2014). Qualitative and quantitative top-down mass spectral analysis of crustacean hyperglycemic hormones in response to feeding.  Invited Contribution to "Top Down Proteomics" Special Issue.  Proteomics. 14, 1185-1194.  doi: 10.1002/pmic.201300331.
  • Z. Zhang, J. Kuang, and L. Li* (2013).  Liquid chromatogrphy-matrix-assisted laser desorption/ionization mass spectrometric imaging with sprayed matrix for improved sensitivity, reproducibility and quantitation.  Analyst138, 6600-6606, DOI: 10.1039/C3AN01225E.
  • D. Frost and L. Li* (2014).  Recent advances in glycoproteomics and its application in biomedicine and pharmacology.  Invited contribution, Advances in Protein Chemistry and Structural Biology95, 71-123.  doi: 10.1016B978-0-12-800453-1.00003-8.
  • E. Gemperline, B. Chen, and L. Li* (2014). Mass spectrometric imaging of neurotransmitters:  challenges and recent advances.  Invited contribution.  Bioanalysis6, 525-540.  doi: 10.4155/bio.13.341.
  • C. Jia, C.B. Lietz, Q. Yu, and L. Li* (2014).  Site-specific characteriation of D-amino acid-containing peptide epimers by ion mobility spectrometry.  Analytical Chemistry. 86, 2972-2981, DOI: 10.1021/ac4033824.  Featured as an ACS Editor's Choice article and on the journal cover.
  • X. Zhong, Z. Zhang, S. Jiang, and L. Li* (2014).  Recent advances in microseparation coupled to mass spectrometric detection.  Invited review.  Electrophoresis35, 1214-1225.  doi: 10.1002/elps.201300451
  • Q. Yu, C. Ouyang, Z. Liang, and L. Li* (2014).  Mass spectrometric characterization of crustacean neuropeptidome.  Invited mini-review.  Special issue on "Peptidomics (stat-of-the-art 2014).  EuPA Open Proteomics3, 152-170.
  • C. Jia, Q. Yu, C. Ouyang, F. Ma, C.M. Schmerberg, and L. Li*(2014).  Rapid and sensitive characterization of neuropeptidome in Dungeness crabs using a Q-Exactive high-resolution mass spectrometer and peptide alterations in response to feeding.  EuPA Open Proteomics.  To be submitted.
  • C. Ouyang, A. Kim, and L. Li* (2014).  Evaluation of neurotoxicity of nanoparticles in decapod crustacean using MS-based peptidomics.  Invited contribution.  Special Issue on "Peptidomics (state-of-the-art 2014). Journal of Proteome Research.  To be submitted.
  • E. Gemperline and L. Li* (2014).  Investigation of metabolites in Medicago truncatula root nodules with MALDI-mass spectrometric imaging.  Invited contribution.  Journal of Visualized Experiments (JoVE).  Mar 5;(85). doi: 10.3791/51434.
  • H. Ye, J. Wang, Z. Zhang, C. Jia, C. Schmerberg, A.D. Catherman, P.M. Thomas, N.L. Kelleher, and L. Li* (2014).  Defining the neuropeptidome of the spiny lobster Panulirus interruptus brain using a multi-dimensional mass spectrometry-based platform.  Journal of Proteome Research.  To be submitted.
  • E. Gemperline, S. Rawson, and L. Li* (2014).  Optimization and comparison of multiple MALDI matrix applicaton methods for small molecule mass spectrometric imaging.  Analytical Chemistry. 86, 10030-10035.  doi: 10.1021/ac5028534. Epub 2014 Oct 10.
  • C. Schmerberg, N. Woodards, and L. Li* (2014).  Recent advances in mass spectrometry of neuropeptides.  Invited contribution. Mass Spectrometry Review.  To be submitted.
  • C. Schmerberg, Z. Liang, and L. Li* (2015).  Data-independent MS/MS quantification of neuropeptides for determination of putative feeding-related neurohormones in microdialysate.  ACS Chemical Neuroscience.  Invited contribution to Special Issue featuring 2014 Monitoring Molecules in Neuroscience Meeting.   Accepted for publication on December 31, 2014.
  • C. Schmerberg, Z. Liang, and L. Li* (2014).  Mass spectrometric characterization of the neuropeptides of the crayfish Orconectes rusticus.  Journal of Proteome Research.  To be submitted.
  • J. Wang, S. Yokoyama, R. Cunningham, X. Sun, and L. Li* (2014).  Comparative analysis of the proteomic changes of amniotic fluid in different gestational age for lung development.  Manuscript in preparation.
  • J. Wang, R. Cunningham, O. Okonkwo, and L. Li* (2014).  Quantitative comparison of cerebrospinal fluid glycoproteins in subjects with Alzheimer's disease, mild cognitive impairment and healthy individuals.  Manuscript in preparation.
  • C. Jia, Z. Wu, C.B. Lietz, Z. Liang, Q. Cui, and L. Li* (2014).  Gas-phase ion isomer analysis reveals the mechanism of peptide sequence scrambling.  Analytical Chemistry. 86, 2917-2924, doi: 10.1021/ac401578p, featured as a cover article.
  • Z. Zhang, S. Jiang, and L. Li* (2013).  Semi-automated liquid chromatography-mass spectrometric imaging platform for enhanced detection and improved data analysis of complex peptide mixtures.   Journal of Chromatography A.  Invited contribution to MSB 2012 Shanghai Special Issue, 1293, 44-50.
  • E.W. Rodgers, W.D. Krenz, X. Jiang, L.Li, and D.J. Baro*(2013).  Dopaminergic tone regulates transient potassium current maximal conductance through a translational mechanism requiring DIRs, cAMP/PKA, Erk and mTOR.  BMC Neuroscience14, 143.  doi:10.1186/1471-2202-14-143.
  • R. Sturm, C. Lietz, and L. Li*(2014).  Improved isobaric mass tag quantification by ion mobility mass spectrometry.  Rapid Communication in Mass Spectrometry28, 1051-1060.