Central to the ability of vascular cells to adhere to the extracellular matrix and to each other is an abundant supply of cell surface adhesion molecules that, in addition to influencing the adhesive phenotype of the cell, are also capable of transmitting signals into, and responding to signals from, the cell interior (often referred to an outside/in and inside/out signal transduction, respectively). Such post-ligand events occur by virtue of the ability of these transmembrane proteins to interact with intracellular kinases and phosphatases, G-proteins, adapter proteins, and cytoskeletal components. Our laboratory divides its attention between exploring the role of stimulatory and inhibitory receptors in regulating adhesion and aggregation of human and murine platelets (funded through a Program Project grant), and the structure and function of PECAM-1 in the blood and vascular cells in which it is expressed (funded through a long-standing R01). Techniques range from biochemistry to molecular biology to whole animal models of thrombosis and hemostasis.
Current Grant Support
NIH Grant R01 HL40926, years 22-26 - Molecular Biology and Function of PECAM-1
NIH Program Project Grant P01-HL44612, years 21-25 (Program Director, Leader, Project 1, and Director of Administrative Core A) - Molecular Mechanisms of Platelet Activation and Adhesion
NIH Postdoctoral Training Grant HL-07209 (Co-PI with GC White)
Ongoing NIH-funded research projects are listed below:
Molecular mechanisms of integrin signaling
Integrin/ITAM coupling in platelets and vascular cells
Role of PECAM-1 adhesion and signaling in endothelial cell barrier function and vascular permeability
Construction of transgenic and knock-in mice expressing variant forms of PECAM-1
In vitro microfluidic models of thrombus formation
Patil S, DK Newman, and PJ Newman: PECAM-1 serves as an inhibitory receptor that modulates platelet responses to collagen. Blood 97:1727-1732, 2001.
Gao C, W Sun, M Christofidou-Solomidou, M Sawada, DK Newman, C Bergom, SM Albelda, S Matsuyama, and PJ Newman: PECAM-1 functions as a specific and potent inhibitor of mitochondrial-dependent apoptosis. Blood 102:169-179, 2003.
Newman PJ, JG McFarland, and RH Aster: Alloimmune Thrombocytopenias. In Thrombosis and Hemorrhage, 3rd Edition, (J. Loscalzo, A. I. Schafer, eds.) Lippincott Williams and Wilkins, Philadelphia, PA., pp. 441-456, 2003.
Rathore V, MA Stapleton, CA Hillery, RR Montgomery, TC Nichols, EP Merricks, DK Newman, and PJ Newman: PECAM-1 negatively regulates GPIb/V/IX signaling in murine platelets. Blood 102:3658-3664, 2003.
Boylan, B, H Chen, V Rathore, C Paddock, M Salacz, KD Friedman, BR Curtis, M Stapleton, DK Newman, and PJ Newman: Anti-GPVI-associated ITP: An acquired platelet disorder caused by autoantibody-mediated clearance of the GPVI/FcRy-chain complex from the human platelet surface. Blood 104:1350-1355, 2004.
Maas M, MA Stapleton, CR Bergom, DL Mattson, DK Newman, and PJ Newman: Endothelial PECAM-1 confers protection against endotoxic shock. Am J Physiol Heart Circ Physiol 288:H159-H164, 2005.
Falati S, S Patil, PL Gross, M Stapleton, G Merrill-Skoloff, NE Barrett, KL Pixton, H Weiler, B Cooley, DK Newman, PJ Newman, BC Furie, B Furie, and JM Gibbins: Platelet PECAM-1 inhibits thrombus formation in vivo. Blood 107:535-541, 2006. PMID: 16166583
Novinska M, BC Pietz, TM Ellis, DK Newman, and PJ Newman: The alleles of PECAM-1. Gene 376:95-101, 2006. PMID: 16581204
Boylan B, MC Berndt, ML Kahn, and PJ Newman: Activation-independent, antibody-mediated removal of GPVI from circulating human platelets: Development of a novel NOD/SCID mouse model to evaluate the in vivo effectiveness of anti-human platelet agents. Blood 108:908-914, 2006. PMID: 16569773
Bergom C, R Goel, C Paddock, C Gao, DK Newman, S Matsuyama, and PJ Newman: The cell-adhesion and signaling molecule PECAM-1 is a molecular mediator of resistance to genotoxic chemotherapy. Cancer Biology & Therapy 5:1699-1707, 2006. PMID: 17106245
Zhu J, B Boylan, B-H Luo, PJ Newman and TA Springer: Tests of the extension and dead-bolt models of integrin activation. J Biol Chem 282, 11914-11920, 2007. PMID 17301049
Boylan B, C Gao, V Rathore, JC Gill, Debra K. Newman, and PJ Newman: Identification of FcγRIIa as the ITAM-bearing receptor mediating αIIbβ3outside-in integrin signaling in human platelets. Blood 112:2780-2786, 2008. PMCID: PMC2556613
Newman PJ and DK Newman: Platelets and the Vessel Wall In Nathan and Oski's Hematology of Infancy and Childhood (7th Edition). Elsevier Press, pp. 1379-1398, 2008.
Goel R, B Schrank, S Arora, B Boylan, B Fleming, H Miura, PJ Newman, RC Molthen, and DK Newman: Site-specific effects of PECAM-1 on atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol 28:1996-2002, 2008. PMID: 18669884
Bakchoul T, B Boylan, UJH Sachs, G Bein, C Ruan, S Santoso, and PJ Newman: Blockade of maternal anti-HPA-1a-mediated platelet clearance by an HPA-1a epitope-specific F(ab')2 in an in vivo mouse model of alloimmune thrombocytopenia. Transfusion 49:265-270, 2009. PMID: 19000229
Gao C, B Boylan, D Bougie, JC Gill, J Birenbaum, DK Newman, RH Aster, and PJ Newman: Eptifibatide-induced thrombocytopenia and thrombosis in humans require FcγRIIa and the integrin β3 cytoplasmic domain. J Clin Invest 119:504-511, 2009. PMCID: PMC2648674
Privratsky JR, BE Tourdot, DK Newman, and PJ Newman: The anti-inflammatory actions of PECAM-1 do not involve regulation of endothelial cell NFκB. J Immunol 184: 3157-63, 2010.
Crockett J, DK Newman, and PJ Newman: PECAM-1 is a negative regulator of laminin-induced platelet activation. J Thromb Haemost 8:1584-1593, 2010.
Privratsky JR, C Paddock, and PJ Newman: Relative contribution of PECAM-1-mediated adhesion and signaling to the maintenance of vascular integrity. J Cell Sci 124:1477, 2011.
Gao C, B Boylan, J Fang, DA Wilcox, DK Newman, and PJ Newman: Heparin promotes platelet responsiveness by potentiating αIIbβ3-mediated outside-in signaling. Blood 117:4946, 2011.
Paddock, CA, B Lytle, F Peterson, T Holyst, PJ Newman, B Volkman, and DK Newman. Residues within a lipid-associated segment of the PECAM-1 cytoplasmic domain are susceptible to inducible, sequential phosphorylation. Blood 117:6012-6023, 2011.