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Research Interests:
The research in Dr. Bodnar's laboratory investigates the regulation of angiogenesis, specifically aiming to identify the resident molecules that can be used to improve the wound healing process and treat diseases resulting from pathological neovascularization. The dysregulation of angiogenesis can lead to a variety of pathological conditions such as diabetic retinopathy, rheumatoid arthritis, endometriosis, pulmonary fibrosis, psoriasis, and also promotes tumor growth. Therefore, the identification of an endogenous inhibitor of angiogenesis that is able to override the angiogenic signals of angiogenic factors will provide novel therapies for the treatment of diseases caused by pathological vascularization.
We are focusing on the ELR-negative chemokines, interferon- inducible protein of 10 kD (IP-10, CXCL10), Interferon-inducible T-cell alpha chemoattractant (ITAC, IP-9, CXCL11), monokine induced by interferon- (Mig, CXCL9) and platelet factor 4 (PF4, CXCL4) that have been observed as having angiostatic properties. However, both their mechanism of action is not understood and what roles they play during tissue repair remain ill-defined. The lab is also investigating the role endothelial cells and angiogenesis play in dermal/epidermal communication during the wound healing process.
The receptor for the ELR-negative chemokines is the CXC receptor 3 (CXCR3). Recently, we were the first to show that activation of CXCR3 inhibits endothelial motility through a PKA mediated pathway. We identified that activation of PKA inhibited m-calpain activity, which is required for VEGF stimulated endothelial migration. Although, we have identified a pathway to inhibit initial vessel growth this does not indicate the mechanism mediating the regression/dissociation of newly formed vessels. Currently we are investigating the molecular pathways that regulate vascular stability. Our current hypothesis is that CXCR3 signaling in endothelial cell of immature vessels activates mu-calpain. Activation of mu-calpain cleaves the cytoplasmic tail of 3 integrin causing the dissociation of the endothelial cells from the matrix causing anoikis.
Selected Publications:
Yates CC, Whaley D, Kulasekeran P, Hancock WW, Lu B, Bodnar RJ, Newsome J, Hebda PA, Wells A,; Delayed and Deficient Dermal Maturation in Mice Lacking the CXCR3 ELR-negative CXC Chemokine Receptor, (2007) American Journal of Pathology (PMID: 17600132)
Bodnar RJ, Yates CC, Wells A, IP-10 blocks VEGF-induced endothelial cell motility and tube formation via inhibition of calpain, (2006) Circulation Research, Vol. 98, p. 617-625
Dia, K, Bodnar RJ, Berndt MC, Du X, A critical role for 14-3-3 protein in regulating the VWF binding function of the platelet glycoprotein Ib-IX and its therapeutic implications, (2005) Blood, Vol. 106 (6), p. 1975-1981
*Gladding A, *Bodnar RJ, Reynolds IJ, Shiraha H, Satish L, Potter DA, Blair HC, Wells A: EGF activates m-calpain (calpain 2), at least in part, by ERK-mediated phosphorylation. (2004) Molecular and Cell Biology, Vol. 24 (6), p. 2499-2512
Xi X, Bodnar RJ, Li Z, Lam CT, Du X; A critical role for the NITY sequence of the integrin b3 cytoplasmic domain in inside-out signaling and its regulation by calpain. (2003) Journal of Cell Biology, Vol. 163, (2) p. 238-249
Bodnar RJ, Xi X, Li Z, Berndt M, Du X, Regulation of glycoprotein Ib-IX-von Willebrand factor interaction by cAMP-dependent protein kinase -mediated phosphorylation at serine 166 of glycoprotein Ib . (2002) Journal of Biological Chemistry, Vol. 277, p. 47080-87
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