Vladimir Y. Toshchakov
Microbiology and Immunology
Bressler Research Building,
- 1983: B.S., Biophysics, Second Moscow Medical Institute, Medico-Biological Department, Moscow, Russia
- 1990: Ph.D., Institute for Transplantation and Artificial Organs, Moscow, Russia
- 1990 – 1994: Laboratory of Organ Preservation, Institute for Transplantation and Artificial Organs, Moscow, Russia
- 2000 – 2002: Postdoctoral Fellow, Department of Microbiology and Immunology, Uniformed Services University of Health Science, Bethesda, MD. Sponsor: Stefanie N. Vogel
- 2002 – present: Research Associate; promoted to Assistant Professor, Department of Microbiology and Immunology, University of Maryland, School of Medicine, Baltimore, MD
The Toll-like Receptors (TLRs) sense the presence of conserved microbial and host "danger" molecules and elicit primary inflammatory responses that mediate host defense. Similarly to many other single-pass transmembrane receptors, the TLRs initiate intracellular signaling through dimerization of intracellular portions of two receptor molecules. Interaction of an agonist with the TLR extracellular domain causes the intracellular Toll-Interleukin-1 Receptor (TIR) domains of two TLRs to come to direct contact. This dimerization event creates a composite binding site to which an adapter protein binds through the TIR domain present in the TLR adapters. Multiple, co-operative interactions of TIR domains of TLRs and TLR adapters eventually result in the formation of large signaling complex that propagates the signal further downstream. Our current primary project aims to identify the TIR domain interfaces that mediate the assembly of TLR signaling complexes. We also develop molecular tools for targeting these interfaces so to inhibit or modulate TLR functions. An additional major area of interest is the development of methods that allow studying the co-operative protein interactions and application of these methods to TIRs and other interaction domains.
- Wenji Piao, Ph.D., Research Associate
- Lisa Ru, B.S., Research Assistant
Lab Techniques and Equipment:
We apply a combination of cell-based, biophysical, and molecular biology approaches in our studies. We have used several in vivo models of inflammatory diseases to preliminary evaluate the drug potential of TLR inhibitors we develop. In collaboration with Drs. Szmacinski and Lakowicz in the Center for Fluorescence Spectroscopy, UMB SOM, we apply Fluorescence Lifetime Imaging Microscopy to study details of protein-protein and protein-peptide interactions in cells. We also collaborate with research group led by Dr. Eric Sundberg, the Institute of Human Virology, UMB SOM to study biophysical aspects of molecular interactions that underlie TLR signaling and inhibition thereof.
Selected peer-reviewed journal articles in reverse chronological order.
- Piao W., Ru L.W., Piepenbrink K.H., Sundberg E.J., Vogel S.N., and Toshchakov V.Y., Recruitment of TLR adapter TRIF to TLR4 signaling complex is mediated by the second helical region of TRIF TIR domain. PNAS 2013 [submitted after revision]
- Piao W., Vogel S.N., Toshchakov V.Y. Inhibition of TLR4 Signaling by TRAM-Derived Decoy Peptides In Vitro and In Vivo. J Immunol. 2013 Mar 1;190(5):2263-72. Epub 2013 Jan 23. PMID: 23345333 PMCID: PMC3578136 [Available on 2014/3/1]
- Szmacinski H., Toshchakov V., Piao W., Lakowicz J.R. Imaging of Protein Secretion from a Single Cell Using Plasmonic Substrates. BioNanoScience March 2013, Volume 3(1), pp 30-36. Epub 2013 Jan 24. PMID: 23814699
- Couture L.A., Piao W., Ru L.W., Vogel S.N., Toshchakov V.Y. Targeting Toll-like receptor (TLR) signaling by Toll/IL-1R domain-containing adapter protein/MyD88-adapter-like- (TIRAP/Mal-) derived decoy peptides. J Biol Chem. 2012 Jul 13;287(29):24641-8. Epub 2012 May 30. PMID: 22648407.
- Liu A., Gong P., Hyun S.W., Wang K.Z., Cates E.A., Perkins D., Bannerman D.D., Puché A.C.., Toshchakov V.Y., Fang S., Auron P.E., Vogel S.N., Goldblum S.E. TRAF6 Protein Couples Toll-like Receptor 4 Signaling to Src Family Kinase Activation and Opening of Paracellular Pathway in Human Lung Microvascular Endothelia. J Biol Chem. 2012 May 11;287(20):16132-45. Epub 2012 Mar 23. PMID: 22447928
- Toshchakov V.Y., Szmacinski H., Couture L.A., Lakowicz J.R., & Vogel S.N. Targeting TLR4 Signaling by TLR4 TIR-derived Decoy Peptides: Identification of the TLR4 TIR Dimerization Interface. J Immunol. 2011 Apr; 186(8), 4819-27. PMID: 21402890.
- Rallabhandi P., Nhu Q.M., Toshchakov V.Y., Piao W, Medvedev A.E, Hollenberg M.D., Fasano A., and Vogel S.N. Analysis of proteinase-activated receptor 2 and TLR4 signal transduction: a novel paradigm for receptor cooperativity. J Biol Chem. 2008 Sep 5; 283(36):24314-25. PMCID: 18622013.
- Toshchakov V.Y., and S.N. Vogel. Cell-penetrating TIR BB loop decoy peptides: a novel class of TLR signaling inhibitors and a tool to study topology of TIR-TIR interactions. Exp. Opin. Biol. Ther. 2007; 7(7), 1035-1050. Review. PMID: 17665992
- Polumuri S.K., V.Y. Toshchakov, and S.N. Vogel. Role of phosphatidylinositol-3 kinase in transcriptional regulation of TLR-induced IL-12 and IL-10 by Fc gamma receptor ligation in murine macrophages. J. Immunol. 2007; 179(1): 236-246. PMID: 17579043.
- Toshchakov V.Y., M.J. Fenton, and S.N. Vogel. Cutting Edge: Differential inhibition of TLR signaling pathways by cell-permeable peptides representing BB loops of TLRs. J Immunol. 2007 Mar 1; 178(5):2655-60. PMID: 17312106.
- Toshchakov V., S. Basu, M.J. Fenton, and S.N. Vogel. Differential Involvement of BB-loops of TIR Domain-Containing Adapter Proteins in Toll-like Receptor (TLR) 4- versus TLR2-Mediated Signal Transduction. J. Immunol. 2005 Jul 1; 175(1): 494-500. PMID: 15972684
- M. Dobrovolskaia, A. E. Medvedev, K. E. Thomas, N. Cuesta, V. Toshchakov, T. Ren, M. J. Cody, S.M. Michalek, N. R. Rice, and S. N. Vogel. Induction of in vitro reprogramming by Toll-like receptor (TLR)2 and TLR4 agonists in murine macrophages: effects of TLR "homotolerance" versus "heterotolerance" on NF-kappa B signaling pathway components. J. Immunol. 2003 Jan; 170(1): 508-19. PMID: 12496438.
- S. H. Rhee, B. W. Jones, V. Toshchakov, S. N. Vogel, and M. J. Fenton. Toll-like receptors 2 and 4 activate STAT1 serine phosphorylation by distinct mechanisms in macrophages. J Biol. Chem. 2003 Jun 20; 278(25): 22506-12. PMID: 12686553.
- V. Toshchakov, B. W. Jones, A. Lentschat, A. Silva, P.-Y. Perera, K. Thomas, M. J. Cody, S. Zhang, B. W. G. Williams, J. Major, T. A. Hamilton, M. J. Fenton, and S. N. Vogel. TLR2 and TLR4 agonists stimulate unique repertoires of host resistance genes in murine macrophages: Interferon-b-dependent signaling in TLR4-mediated responses. J. Endotoxin Res. 2003; 9(3): 169-175. PMID: 12831458.
- Toshchakov V, Jones BW, Perera P-Y, Thomas K, Cody MJ, Zhang S, Williams BRG, Major J, Hamilton TA, Fenton MJ, Vogel SN. TLR4, but not TLR2, mediates IFN-b-induced STAT1 a/b-dependent gene expression in macrophages. Nature Immunol. 2002 April; 3(4); 392-8. PMID: 11896392.
- Hirschfeld M, Weis JJ, Toshchakov V, Salkowski CA, Cody MJ, Ward DC, Qureshi N, Michalek SM, Vogel SN. Signaling by toll-like receptor 2 and 4 agonists results in differential gene expression in murine macrophages. Infect. Immun. 2001 Mar; 69(3):1477-82. PMID: 11179315.
- Toshchakov VY, Bashkina LV, Shumakov VI. Investigation of possible participation of nucleoside transport systems in the postischemic release of purines and pyrimidines from cold stored liver. Cryobiology. 1999 Jun;38(4): 261-72. PMID: 10413569.
- Toshchakov VY, Bashkina LV, Vityazev GA, Shumakov VI. Adenosine transport in liver before and after organ preservation. Biochemistry (Moscow). 1999 Jun; 64(6): 714-7. PMID: 10395988.
- Toshchakov VY, Bashkina LV, Onishchenko NA, Shumakov VI. An isocratic, reversed-phase HPLC method for the determination of postischemic efflux of purines and pyrimidines during reperfusion of isolated liver. Biochemistry (Moscow). 1998 Feb;63(2):219-23. PMID: 9526118.