Research
Overall Goals of the Research Program of the Laboratory
The main area of my research is the elucidation of the molecular events that dictate the course of healing and especially inflammation and angiogenesis following the implantation of biomaterials and scaffolds for tissue engineering applications. Our primary research focus is on three molecules, MCP-1, MMP-9, and thrombospondin (TSP)-2 that we have shown to be critical to various aspects of these processes. In addition, through the process of molecular dissection of cell-matrix interactions, we aim to incorporate rational design in the development of bioengineering applications such as tissue-engineered vascular grafts.
My laboratory is also focused on elucidating the mechanism through which the endogeno us inhibitor of angiogenesis TSP-2 limits angiogenesis and art eriogene sis. We are utilizing an in vitro, TSP-2-sensitive, three-dimensional angiogenesis assay and we are currently investigating the effects of TSP-2 on endothelial cells. Our aim is to identify the signaling pathways that mediate the anti-angiogenic effect of TSP2. We have recently shown that TSP2 is critical for the recovery of blood flow in an experimental model of hindlimb ischemia, predominantly through enhanced arteriogenesis in the upper limb and increased angiogenesis in the lower limb. Finally, we are working on translating our basic findings regarding TSP2 function into a strategy for the generation of matrix-coated synthetic vascular grafts. Based on the assumption that a TSP2-null-derived matrix could confer anti-thrombotic and pro-angiogenic properties to the luminal surface of synthetic vessels, we have pursued several in vitro and in vivo studies in order to provide proof-of-principle for our hypothesis. Specifically, we have found that the TSP 2-null-derived matrix is more permissive for endothelial cell migration and compromised in its ability to induce platelet activation. Furthermore, transplantation of denuded aortic segments from TSP2-null to wild type mice indicates that they are resistant to thrombosis and, unlike transplanted wild type segments, remain patent in the long term.
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People
Current members of the Kyriakides laboratory:
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Themis Kyriakides, Principal Investigator |
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Eleni Skokos, Research Associate/Lab Manager |
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Weiming Tian, Postdoctoral Fellow |
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Susan MacLauchlan, Graduate Student in Pathology |
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Antonios Charokopos, BS/MS Student in Molecular Biology |
Sarah Foote, Undergraduate Student in Molecular Biology (MCDB) |
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Publications
Selected Recent Publications:
Cahn F., Kyriakides T.R. Generation of an artificial skin construct containing
a non-degradable fiber mesh: a potential transcutaneous interface. Biomedical
Materials (in press)
Krady M.M., Zeng J., Yu J., MacLauchlan S, Skokos E.A., Bornstein P., Sessa
W.C., Kyriakides T.R. Thrombospondin-2 modulates extracellular matrix remodeling
during physiologic angiogenesis. American Journal of Pathology 173(3):879-91.
2008.
Jay, S.M., Skokos, E., Laiwalla*, F., Krady, M.M., Kyriakides, T.R. Foreign
Body Giant Cell Formation Is Preceded by Lamellipodia Formation and Can Be Attenuated
by Inhibition of Rac1 Activation. American Journal of Pathology, 171:
2, 2007.
Kyriakides, T. R., M.J. Foster*, G.E. Keeney*, A. Tsai, C.M. Giachelli, I. Clark-Lewis,
B.J. Rollins, P. Bornstein. The CC chemokine ligand, CCL2/MCP1, participates
in macrophage fusion! and foreign body giant cell formation. Am. J. Pathol. 165:
2157-2166. 2004.
Kyriakides, T.R., Cheung, C.Y., Murthy, N., Bornstein, P., Stayton, P.S., and
Hoffman, A.S. pH-sensitive polymers that enhance intracellular drug delivery
in vivo. J. Controlled Release 78:295-303, 2002.
Kyriakides, T.R., Zhu, Y-H., Yang, Z., Huynh, G*., and Bornstein, P. Altered
extracellular matrix remodeling and angiogenesis in sponge granulomas of TSP2-null
mice. Am. J. Pathology 159:1255-1262, 2001.
Kyriakides, T.R., Hartzell, T.*, Huynh, G., and Bornstein, P. Regulation of
angiogenesis and matrix remodeling by localized, matrix-mediated antisense gene
delivery. Molecular Therapy 3:842-849, 2001.
Kyriakides, T. R., Leach, K. J., Hoffman, A. S., Ratner, B. D., and Bornstein,
P. Mice that lack the angiogenesis inhibitor, thrombospondin 2, mount an altered
foreign body reaction characterized by increased vascularity. P! roc. Natl.
Acad. Sci. USA 96:4449-4454. 1999
Kryriakide s,T.R., T. Papayannopoulou, P. Rojnuckarin, K. Kaushansky, M. A.
Reidy, K. Hankenson, P. Bornstein. Uptake of TSP2 by megakaryocytes: An important
determinant of platelet formation and function. Blood 101:3915-3923,
2003.
Kyriakides, T. R., Tam, J. W. Y.* and Bornstein, P. (1999) Accelerated wound
healing in mice with a disruption of the thrombospondin 2 gene. J. Invest.
Dermatology 113:782-787.
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