Cell adhesion molecules, such as ICAM and PECAM, help mediate cell cell interactions. For instance, when an immune cell (such as a neutrophil) encounters an endothelial cells at a site of inflamation, ICAM helps the two cells bind to each other and enables neutrophil transmigration. In addition to the physiological roles for cell adhesion molecules, these proteins also are useful targets for endothelial cell-specific drug targeting. We had previously observed that monomeric anti-ICAM was not endocytosed by endothelial cells, however, multimeric antibody conjugates were readily internalized and had therapeutic benefits. Using a combination of molecular and pharmacologic approaches to further define the mechanism of antibody conjugate uptake, we found that crosslinking ICAM stimulates endocytosis via a previously undescribed pathway. Some of the properties of this endocytic pathway, such as the long lifetime of internalized antibody conjugates, are advantageous for the design of drug delivery vehicles. Future studies will further define the signalling pathways that stimulate plasma membrane turnover in response to ICAM clustering. Also, roles for ICAM-stimulated membrane turnover in processes such as immune cell transmigration and scavenging apoptotic bodies from the blood stream are being explored.
Projects include:
Defining the molecular basis for regulating ICAM and PECAM internalization and sorting.
Defining ICAM and PECAM motifs which regulate endothelial responses to clustering
Examining effect of CAM clustering on other junctional complexes in cells (such as tight junctions).
Using insights from mechanisms regulated CAM uptake and turnover to optimize immunotargeted nanoparticles as potential therapeutic agents.
Selected References
Garnacho, C., V. Shuvaev, A. Thomas, L. MacKenna, M. Koval, S. Albelda, S. Muro and V. Muzykantov. 2008. Activation and recruitment of RhoA induced by anti-PECAM nanocarriers during CAM-mediated endocytosis: critical role for tyrosine 686 in the cytoplasmic tail of PECAM-1. Blood, 111:3024-3033. (PubMed)
Dzubila, T., S. Muro, V. R. Muzykantov and M. Koval. 2006. Nanoscale Anti-Oxidant Therapeutics. in Oxidative Stress, Disease and Cancer, Keshav K. Singh, editor. Imperial College Press, London, pp 1023-1044.
Muro S., M. Mateescu, C. Gajewski, M. Robinson, V. R. Muzykantov, M. Koval. 2006. Control of intracellular trafficking of ICAM-1-targeted nanocarriers by
endothelial Na+/H+ Exchanger (NHE) proteins. Am J Physiol Lung Cell Mol Physiol. 290:L809-817. (PubMed).
Fries D.M., R. Lightfoot, M. Koval and H. Ischiropoulos. 2005. Autologous Apoptotic Cell Engulfment Stimulates Chemokine Secretion by Vascular Smooth Muscle Cells. Am. J. Pathol. 167:345-353. (PubMed).
Muro, S., C. Gajewski, M. Koval and V. R. Muzykantov. 2005. ICAM-1 recycling in endothelial cells: a novel pathway for sustained intracellular delivery and prolonged effects of drugs, Blood. 105:650-658.(PubMed).
Muro, S., M. Koval and V. R. Muzykantov. 2004. Mechanisms for drug targeting to vascular endothelium. Curr. Vasc. Pharm., Curr. Vasc. Pharm. 2:281-299.(PubMed)
Muro, S., X. Cui, C. Gajewski, J.C. Murciano, V.R. Muzykantov, and M. Koval. 2003. Slow intracellular trafficking of catalase nanoparticles targeted to ICAM-1 protects endothelial cells from oxidative stress. Am J Physiol Cell Physiol. 285:C1339-47.(PubMed).
Muro, S., R. Wiewrodt, L. Koniaris, A. P. Thomas, S. M. Albelda, V. Muzykantov and M. Koval. A novel endocytic pathway induced by clustering endothelial ICAM-1 or PECAM-1. 2003. J. Cell Sci., 116:1599-1609. (PubMed)
Wiewrodt, R., A. P. Thomas, L. Cipelletti, D. A. Weitz, S. M. Albelda, M. Koval and V. Muzykantov. 2002. Size-dependent intracellular immunotargeting into endothelial cells via a surface adhesion molecule, PECAM-1. Blood, 99:912-922. (PubMed)
Koval, M., K. Preiter, C. Adles, P. D. Stahl, and T. H. Steinberg. 1998. Size of IgG-opsonized particles determines macrophage response during internalization. Exp. Cell Res., 242:265-273.
(PubMed)
Koval, M. 1993. Plasma membrane lipid transport in cultured cells: Studies using lipid analogs and model systems. Adv. in Cell and Molec. Biol. of Membr. 1:199-224.
Koval, M., and R. E. Pagano. 1991. Intracellular transport and metabolism of sphingomyelin. Biochim. Biophys. Acta 1082:113-125. (PubMed)
Koval, M., and R. E. Pagano. 1990. Sorting of an internalized plasma membrane lipid between recycling and degradative pathways in normal and Niemann-Pick, type A fibroblasts. J. Cell Biol. 111:429-442.
(PubMed)
Koval, M., and R. E. Pagano. 1989. Lipid recycling between the plasma membrane and intracellular compartments: Transport and metabolism of fluorescent sphingomyelin analogues in cultured fibroblasts. J. Cell Biol. 108:2169-2181.
(PubMed)
Cell adhesion molecules, such as ICAM and PECAM, help mediate cell cell interactions. For instance, when an immune cell (such as a neutrophil) encounters an endothelial cells at a site of inflamation, ICAM helps the two cells bind to each other and enables neutrophil transmigration. In addition to the physiological roles for cell adhesion molecules, these proteins also are useful targets for endothelial cell-specific drug targeting. We had previously observed that monomeric anti-ICAM was not endocytosed by endothelial cells, however, multimeric antibody conjugates were readily internalized and had therapeutic benefits. Using a combination of molecular and pharmacologic approaches to further define the mechanism of antibody conjugate uptake, we found that crosslinking ICAM stimulates endocytosis via a previously undescribed pathway. Some of the properties of this endocytic pathway, such as the long lifetime of internalized antibody conjugates, are advantageous for the design of drug delivery vehicles. Future studies will further define the signalling pathways that stimulate plasma membrane turnover in response to ICAM clustering. Also, roles for ICAM-stimulated membrane turnover in processes such as immune cell transmigration and scavenging apoptotic bodies from the blood stream are being explored.