I received my PhD in Biochemistry and Molecular Biology and also had my postdoctoral training at the University of Notre Dame, Notre Dame, Indiana. I joined the faculty of the University of Maryland, School of Medicine in 2004 as an Associate Professor. My research program has been continuously funded and supported by the National Institute of Health and the American Heart Association. I'm also associated with a training grant from the National Institute of Health.
Stem cells possess the ability to self-renew and to differentiate into multiple tissue types, and thus are ideal source of cells for tissue repair and regeneration. However, successful stem cell-based tissue regeneration depends on our ability to prepare a homogenous stem cell population and to overcome tissue rejection mediated by host immune cells. Thus, our research program comprises two separate projects: one is focused on the roles of mesenchymal stem cells in tissue repair/regeneration and the other is to study the roles of leukocytes in physiological processes, e.g. innate and adaptive immune responses, and in disease development, e.g. atherosclerosis, myocardial infarction, stroke, and osteoporosis.
The long term goal of our research is to better understand the biology of leukocyte integrins, especially the CD18 integrin subfamily, and their roles in both physiological and pathological processes. In particular, our studies will focus on the molecular mechanisms that allow leukocytes to migrate within inflammatory environments (Fig. 1) and to recognize a wide range of physiological and pathological targets via integrin receptors. In addition, based on our recent finding that the CD18 integrin is also expressed by the primitive stromal stem cells and can be used as a cell marker to enrich the stem cell population from total human bone marrow (Fig. 2), we will study the role of CD18 in stromal stem cell proliferation and differentiation, tissue repair and regeneration, as well as its role in the maintenance of a niche microenvironment that is critical to the function of hematopoietic stem cells. The information generated from these studies can be used to assist us in the design of therapeutic reagents that will selectively target the deleterious effects of leukocyte engagement, such as their contributions to pathogenesis of atherosclerosis, arthritis, and other autoimmune diseases, while keeping its host defense functions intact. It can also assist the isolation and enrichment of stromal stem cells for clinical applications.
Our current research interests include:
- Structure-function studies of the CD18 integrins: the molecular basis of integrin ligand binding and integrin activation.
- Macrophage trafficking during inflammation and its resolution.
- Tissue repair and regeneration using stromal stem cells.
- Identification of an unknown mutation in a human patient that causes defective integrin activation.
Lab Techniques and Equipment
- Various knockout and transgenic mice for evaluating the roles of different proteins and receptors in health and disease.
- Commonly used mouse models in the laboratory
- Balloon angioplasty model
- melanoma tumor growth model
- ectopic bone and bone marrow regeneration
- oral and intravenous immune tolerance model
- Adoptive cell transfer and bone marrow transplantation to study the contribution of a particular protein, surface receptor or cell population in leukocyte functions;
- Laser scanning confocal fluorescence microscopy and FRET to study protein interactions;
- Live cell imaging to study cell migration;
- FACS cell sorting to enrich a particular stem cell population;
- Real time RT-PCR, 2D PAGE, and Mass spectroscopy to study gene expression;
- Protein expression in E.coli, Sf9 insect cells, and yeasts, as well as adherent and suspension eukaryotic cells.
- Chunzhang Cao (postdoctoral fellow) Study of macrophage trafficking
- Driss Ehirchiou (postdoctoral fellow) Study of immune regulation
1. Zhang, L. and Castellino, F.J. (1989) Generation of an antibody with a designed specificity difference for protein C and activated protein C. Journal of Protein Chemistry, 8:471-480.
2. Zhang, L. and Castellino, F.J. (1990) A g-carboxyglutamic acid (g variant g6D,g7D) of human activated protein C displays greatly reduced activity as an anticoagulant. Biochemistry, 29:10828-10834.
3. Zhang, L. and Castellino, F.J. (1991) The role of the hexapeptide disulfide loop present in g-carboxyglutamic acid domain of human activated protein C in its in vitro anticoagulant properties. Biochemistry, 30: 6696-6704.
4. Zhang, L., Jhingan, A., and Castellino, F.J. (1992) Role of individual g-carboxyglutamic acid residues of activated human protein C in defining its in vitro anticoagulant activity. Blood, 80: 942-952.
5. Zhang, L. and Castellino, F.J. (1992) Influence of specific g-carboxyglutamic acid residues on the integrity of the calcium-dependent conformation of human protein C. Journal of Biological Chemistry, 267: 26078-26084.
6. Zhang, L. and Castellino, F.J. (1993) The contributions of individual g-carboxyglutamic acid residues in the calcium-dependent binding of recombinant human protein C to acidic phospholipid vesicles. Journal of Biological Chemistry, 268: 12040-12045.
7. Yu. S., Zhang, L., Jhingan, A., Christiansen, W.T. and Castellino, F.J. (1994) Construction, expression, and properties of a recombinant chimeric human protein C with replacement of its growth factor-like domains by those of human coagulation factor IX. Biochemistry, 33: 823-831.
8. Zhang, L., and Castellino, F.J. (1994) The binding energy of human coagulation protein C to acidic phospholipid vesicles contains a major contribution from leucine 5 in the g-carboxyglutamic acid domain. Journal of Biological Chemistry, 269: 3590-3595.
9. Jhingan, A., Zhang, L., Christiansen, W.T. and Castellino, F.J. (1994) The activities of recombinant g-carboxyglutamic acid-deficient mutants of activated human protein C toward human coagulation factor Va and factor VIII in purified systems and in plasma. Biochemistry, 33: 1869-1875.
10. Zhang, L., Muchowski, P.J., Chang, E.R., Soule, H.R., Plow, E.F. and Moyle, M. (1994) Functional interaction between the integrin antagonist NIF and the I domain of CD11b/CD18. Journal of Biological Chemistry, 269: 26419-26423.
11. Zhang, L., and Plow, E.F. (1996) Overlapping, but not identical, sites are involved in the recognition of C3bi, neutrophil inhibitory factor, and adhesive ligands by the CD11b/CD18 integrin. Journal of Biological Chemistry, 271: 18211-18216.
12. Zhang, L., and Plow, E.F. (1996) A discrete site modulates activation of I domains: application to integrin aMb2. Journal of Biological Chemistry, 271: 29953-29957.
13. Zhang, L., and Plow, E.F. (1997) Identification and reconstruction of the binding site within aMb2 for a specific and high affinity ligand, NIF. Journal of Biological Chemistry. 272: 17558-17564.
14. Plow, E.F. and Zhang, L. (1997) A MAC-1 attack: integrin functions directly challenged in knock-out mice. Journal of Clinical Investigation 99:1145-1146.
15. Zaffran, Y., Zhang, L., and Ellner J.J. (1998) Role of CR4 in mycobacterium tuberculosis human macrophages binding and signal transduction in the absence of serum. Infection and Immunity, 66(9): 4541-4.
16. Forsyth, C.B., Plow, E.F., and Zhang, L. (1998) Interaction of the fungal pathogen Candida Albicans with integrin CD11b/CD18: Recognition by the I domain is modulated by the lectin-like domain and the CD18 subunit. Journal of Immunology, 161: 6198-6205.
17. Ugarova, T.P., Solovjov, D.A., Zhang, L., Loukinov, D.I., Yee, V.C., Medved, L.V., and Plow, E.F. (1998) Identification of a novel recognition sequence for integrin aMb2 within the g-chain of fibrinogen. Journal of Biological Chemistry, 273: 22519-22527.
18. Cierniewski, C.S., Byzowa, T., Papierak, M., Haas, T.A., Niewiarowska, J., Zhang, L., Cieslak, M., and Plow, E.F. (1999) Peptides that mimic natural contact points of fibrinogen for aIIbb3 bind simultaneously to distinct subsites on the receptor and induce differential conformational and microenvironmental changes. Journal of Biological Chemistry, 274: 16923-16932,
19. Zhang, L. (1999) The aMb2 integrin and its role in neutrophil function. Cell Research 9:171-178.
20. Zhang, L., and Plow, E.F. (1999) Amino acid sequences within the alpha subunit of integrin aMb2 (Mac-1) critical for specific recognition of C3bi. Biochemistry, 38: 8064-8071.
21. Simon, D.I., Chen, Z., Xu, H., Li, C.Q., Dong, J., McIntire, L.V., Ballantyne, C.M., Zhang, L., Furman, M.I., Berndt, M.C., and Lopez, J.A. (2000) Platelet glycoprotein ibalpha is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). Journal of Experimental Medicine 192:193-204.
22. Simon, D.I., Wei, Y., Zhang, L., Rao, N.K., Xu, H., Chen, Z., Liu, Q., Rosenberg, S., and Chapman, H.A. (2000) Identification of a urokinase receptor-integrin interaction site: promiscuous regulator of integrin function. Journal of Biological Chemistry, 275: 10228-10234.
23. Plow, E.F., Haas, T.A., Zhang, L., Loftus, J. and Smith, J.W. (2000) Ligand binding to integrins. Journal of Biological Chemistry 275:21785-21788.
24. Yakubenko, V.P., Solovjov, D.A., Zhang, L., Yee, V.C., Plow, E.F., and Ugarova, T.P. (2001) Identification of the binding site for fibrinogen recogntion peptide g383-395 within the aMI-domain of integrin aMb2. Journal of Biological Chemistry, 276: 13995-14003.
25. Xiong, Y. M., and Zhang, L. (2001) Structure-function of the putative I-domain within the integrin b2 subunit. Journal of Biological Chemistry, 276: 19340-19349.
27. Cierniewska-Cieslak, A., Cierniewski, C.S., Blecka, K., Papierak, M., Michalec, L., Zhang,L., Haas, T.A., and Plow, E.F. (2002) Identification and characterization of two cation binding sites in the integrin beta 3 subunit. Journal of Biological Chemistry, 277: 11126-11134.
28. Castellino, F.J., Ploplis, V.A. and Zhang, L. (2002) g-glutamate and b-Hydroxyaspartate in Proteins. Posttranslational Modifications of Proteins: Tools for Functional Proteomics. Edited by C. Kannicht, Chapter 17, page 259-268.
29. Li, Y. and Zhang, L. (2003) The fourth blade within the beta-propeller is involved specifically in C3bi recognition by integrin alphaM beta2. Journal of Biological Chemistry 278:34395-34402.
30. Xiong, Y. M., Chen, J., and Zhang, L. (2003) Modulation of CD11b/CD18 adhesive activity by its extracellular membrane-proximal regions. Journal of Immunology 171:1042-1050.
31. Li, Y., D.A. Lawrence, D.A., and Zhang, L. (2003) Sequences within Domain II of the Urokinase Receptor Critical for Differential Ligand Recognition. Journal of Biological Chemistry 278: 29925-29932.
33. Cao, C., Lawrence, D.A., Strickland, D., and Zhang, L. (2005) A specific role of integrin mac-1 in accelerated macrophage efflux to the lymphatics. Blood, 106: 3234-3241, 2005. Also see commentary “Mac-1 mediates migration to lymph nodes” by Joseph P. Mizgerd (Blood 106:2927-2928).
34. Yakovlev, S., Zhang, L., Ugarova, T., and Medved, L. (2005) Interaction of Fibrin(ogen) with Leukocyte Receptor alpha(M)beta(2) (Mac-1): Further Characterization and Identification of a Novel Binding Region within the Central Domain of the Fibrinogen gamma-Module. Biochemistry 44:617-26.
35. Miura, Y., Miura, M., Gronthos, S., Allen, M.R., Cao, C., Uveges, T.E., Bi, Y., Shi, S., and Zhang, L. (2005) Integrin beta2 is a novel surface marker for bone marrow stromal stem cells and plays an important role in osteogenic differentiation in vivo. Proceedings of the National Academy of Sciences 102:14022-14027. see Report on SOM news vol7 number 4, page 2.
36. Cao, C., Lawrence, Li, Y., Von Arnim, C.A., Herz, J., Hyman, B.T., D.A., Strickland, D., and Zhang, L. (2006) Fibrinolytic inhibitor PAI-1 and endocytic receptor LRP coordinate Mac-1-dependent macrophage migration into the lymphatic system. EMBO J 2006, 25:1860–1870.
37. Cao, C., Lawrence, D.A., Li, Y., Von Arnim, C.A., Herz, J., Su, EJ, Makarova, A, Hyman, B.T., D.A., Strickland, D., and Zhang, L. (2006) Endocytic receptor LRP together with tPA and PAI-1 coordinates Mac-1-dependent macrophage migration. The EMBO Journal, 25:1860-1870.
38. Xiong, Y., Cao, C., Makarova, A., Hyman, B., and Zhang, L. (2006) Mac-1 promotes FcgRIIA-dependent cell spreading and migration on immune complexes. Biochemistry 45:8721-31.
39. Miura, Y., Gao, Z., Miura, M., Seo, B.M., Sonoyama, W., Chen, W., Gronthos, S., Zhang, L., and Shi, S. (2006) Mesenchymal Stem Cell-Organized Bone Marrow Elements: An Alternative Hematopoietic Progenitor Resource. Stem Cells 24:2428-2436.
40. Tang, P., Cao, C., Xu, M., and Zhang, L. (2007) Regulation of integrin activation by cytoskeletal protein Radixin. FEBS Letters 581:1103-1108.
41. Ehirchiou, D., Xiong, Y., Xu, G., Chen, W., Shi, Y., and Zhang, L. (2007) CD11b Facilitates the Development of Peripheral Tolerance by Suppressing Th17 Differentiation. Journal Experimental Medicine 204:1519-24.
- see Commentary by Bashyam "CD11b tunes tolerance" J Exp Med 204:1504.
- see Commentary by Budde "The Behavior of Th17 Cells Is Intolerable" CELL 130:7, 2007
- see News and Commentary by Veldhoen "Oral Tolerance: Passing CD11b on the Way to Tolerance" Immunology and Cell Biology85:397-398.
42. Bi, Y., Ehirchiou, D., Kilts, T.M., Inkson, C.A., Embree, M.C., Sonoyama, W., Li, L., Leet, A.I., Seo, B., Zhang, L., Shi, S., and Young, M.F. (2007) Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nature Medicine. 13:1219-1227.
43. Choi, E.Y., Orlova, V.V., Fagerholm, S.C., Nurmi, S.M., Zhang, L., Ballantyne, C.M., Gahmberg, C.G., Chavakis, T. (2008) Regulation of LFA-1-dependent inflammatory cell recruitment by Cbl-b and 14-3-3 proteins. Blood 111:3607-14. PMCID: PMC2275024
44. Li, Y., Cao, C., Jia, W., Yu, L., Mo, M., Wang, Q., Huang, Y., Lim, J., Ishihara, M., Wells, L., Azadi, P., Robinson, H., He, Y., Zhang, L. and Mariuzza, R.A. (2009) Structure of the F-spondin domain of mindin, an integrin ligand and pattern recognition molecule. EMBO J. 28:286-97. PMCID: PMC2637340
45. Malinin, N., Zhang, L., Choi, J., Ciocea, A., Razorenova, O., Ma, Y., Podrez, E.A., Tosi, M., Lennon, D.P., Caplan, A.I., Shurin, S.B., Plow, E.F., and Byzova, T.V. (2009) A point mutation in kindlin-3 ablates activation of three integrin subfamilies in humans. Nature Medicine 15:313-8. PMCID: PMC2857384
46. Danese, S., Vetrano, S., Zhang, L., Poplis, V.A., Castellino, F.J. (2010) The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications. Blood 115:1121-30. PMCID: PMC2920225
47. Bi, Y., Gao, Y., Ehirchiou, D., Cao, C., Kikuiri, T., Le, A., Shi, S., and Zhang, L. (2010) Bisphosphonates Cause Osteonecrosis of the Jaw-like Disease in Mice. American Journal of Pathology, 177:280-90, 2010. PMCID: PMC2893671
48. Cao, C., Gao, Y., Li, Y., Antalis, T., Castellino, F.J., and Zhang, L. (2010) The Efficacy of Activated Protein C in Murine Endotoxemia Is Dependent on Integrin CD11b. Journal of Clinical Investigation 120:1971-1980, Highlighted on Faculty of 1000 Biology, July 2010. PMCID: PMC2877939
49. Ranganathan, S., Cao, C., Catania, J., Migliorini, M., Zhang, L.#, and Strickland, D. K#. Molecular Basis for the Interaction of Low Density Lipoprotein Receptor-related Protein 1 (LRP1) with Integrin αMβ2: IDENTIFICATION OF BINDING SITES WITHIN αMβ2 FOR LRP1. J Biol Chem 286:30535-30541, 2011. #, co-corresponding authors. PMCID: PMC3162413
50. Yakovlev, S., Gao, Y., Cao, C., Chen, L., Strickland, D. K., Zhang, L. #, and Medved, L#. Interaction of fibrin with VE-cadherin and anti-inflammatory effect of fibrin-derived fragments. J.Thromb.Haemost. 9:1847-1855, 2011. #, co-corresponding authors. PMCID: PMC3166367
51. Wolf, D., Hohmann, J.D., Wiedemann, A., Bledzka, K., Blankenbach, H., Marchini, T., Gutte, K., Zeschky, K., Bassler, N., Hoppe, N., Rodriguez, A.O., Herr, N., Hilgendorf, I., Stachon, P., Willecke, F., Duerschmied, D., von Zur Muhlen, C., Soloviev, D.A., Zhang, L., Bode, C., Plow, E.F., Libby, P., Peter, K., Zirlik, A. (2011) Binding of CD40L to Mac-1's I-Domain Involves the EQLKKSKTL Motif and Mediates Leukocyte Recruitment and Atherosclerosis--But Does Not Affect Immunity and Thrombosis in Mice. Circ Res. 109:1269-79. PMCID: PMC3291815
52. Yakovlev, S., Mikhailenko, I., Cao, C., Zhang, L., Strickland, D.K., Medved, L. (2012) Identification of VLDLR as a novel endothelial cell receptor for fibrin that modulates fibrin-dependent transendothelial migration of leukocytes. Blood 119:637-44. PMCID: PMC3257021