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Debra K. Newman, PhD

Debra K. Newman, PhD

Senior Investigator

Professor
Department of Pharmacology & Toxicology
Department of Microbiology and Immunology
Medical College of Wisconsin

Education and training

Doctoral Training
PhD, Marquette University, 1989

Contact Us

Debra K. Newman, PhD

Senior Investigator
Email (414) 937-3820 Fax: (414) 937-6284

  • Research Interests

    Thrombosis, Hemostasis and Vascular Biology

    Platelets are important in early wound healing, where they initially adhere to the extracellular matrix that underlies damaged blood vessels and then aggregate with one another to form a platelet plug. Excessive bleeding occurs when platelet counts are low, or when platelet activity is compromised. Children, especially neonates, who underdo cardiac surgery for repair of congenital heart defects experience excessive bleeding at higher rates than do adults undergoing similar surgeries. We seek to determine the extent to which deficiencies in platelet number or function contribute to excessive bleeding in the setting of pediatric cardiac surgery. This research will help physicians identify pediatric cardiac surgery patients who are at risk for bleeding and administer appropriate blood products in a timely manner should bleeding need to be controlled in this setting.

    A major focus of research in our laboratory is Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1). PECAM-1 is an inhibitory molecule that functions in two important contexts. First, PECAM-1 dampens platelet aggregation in response to low levels of stimulation, which is important to prevent pathological thrombosis. Second, PECAM-1 inhibits T cell responses and interferes with the ability of T cells to kill tumors. We have recently discovered that the ability of PECAM-1 to inhibit T cell anti-tumor responses depends on Transforming Growth Factor β (TGFβ), which is another potent T cell suppressor. Our current work is dedicated to development of a better understanding of how PECAM-1 and TGFβ work together to inhibit T cell responses. This research will help us improve T cell-based therapies for treatment of cancer.

  • Grant Support

    NIH, R35-HL139937 (Co-Investigator), ‘Basic Investigation & Translational Applications Concerning the Cell & Molecular Biology of Blood & Vascular Cells (2018-2024)

     

  • Lab

    Guoping Fu
    Research Associate II

    Marjorie Kipp
    Research Technologist

  • Publications
    • Patil, S., D.K. Newman and P.J. Newman. 2001. PECAM-1 serves as an inhibitory receptor that modulates platelet responses to collagen. Blood 97:1727-32.
    • Newman, D.K., C. Hamilton, M.J. Armstrong and P.J. Newman. 2001. Inhibition of antigen-receptor signaling by platelet endothelial cell adhesion molecule-1 (CD31) requires an intact ITIM, SHP-2, and p56lck. Blood 97:2351-7.
    • Newman, D.K., S. Hoffman, T. Zhao, S. Kotamraju, B. Wakim, B. Kalyanaraman, and P.J. Newman. 2002. Nitration of ITIM tyrosines abrogates phosphorylation and ability to bind SHP-2. Biochemical and Biophysical Research Communications 296:1171-9.
    • Gao, C., W. Sun, M. Christofidou-Solomidou, M. Sawada, D.K. Newman, C. Bergom, S.M. Albelda, S. Matsuyama and P.J. Newman. 2003. PECAM-1 functions as a specific and potent inhibitor of mitochondrial apoptosis. Blood 102:169-79.
    • Newman, P.J. and D.K. Newman. 2003. Signal transduction pathways mediated by PECAM-1: New roles for an old molecule in platelet and vascular biology. Arteriosclerosis, Thrombosis and Vascular Biology 23:953-64.
    • Rathore, V., M.A. Stapleton, C.A. Hillery, R.R. Montgomery, T.C. Nichols, E.P. Merricks, D.K. Newman and P.J. Newman. 2003. PECAM-1 negatively regulates GPIb/V/IX signaling in murine platelets. Blood 102:3658-64.
    • Maas, M., R. Wang, C. Paddock, P.J. Newman and D.K. Newman. 2003. Reactive oxygen species induce reversible PECAM-1 tyrosine phosphorylation and SHP-2 binding. American Journal of Physiology: Heart and Circulatory Physiology 285: H2336–H2344.
    • Boylan, B., H. Chen, V. Rathore, C. Paddock, M. Salacz, K.D. Friedman, B.R. Curtis, M. Stapleton, D.K. Newman, M.L. Kahn and P.J. Newman. 2004. Anti-GPVI-associated ITP: An acquired platelet disorder caused by autoantibody-mediated clearance of the GPVI/FCRγ-chain complex from the human platelet surface. Blood 104:1350-5.
    • Rathore, V., D. Wang, D.K. Newman and P.J. Newman. 2004. Phospholipase Cγ2 contributes to stable thrombus formation on VWF. FEBS Letters 573:26-30.
    • Maas, M., M. Stapleton, C. Bergom, D.L. Mattson, D.K. Newman and P.J. Newman. 2005. Endothelial cell PECAM-1 confers protection against endotoxic shock. American Journal of Physiology: Heart and Circulatory Physiology 288:H159-64.
    • Falati, S., S. Patil, P.L. Gross, M. Stapleton, G. Merrill-Skoloff, N.E. Barrett, K.L. Pixton, H. Weiler, B. Cooley, D.K. Newman, P.J. Newman, B.C Furie, B. Furie, and J.M. Gibbins. 2006. Platelet PECAM-1 inhibits thrombus formation in vivo. Blood 107:535-541.
    • Liu, Y., A.B. Bubolz, Y. Shi, P.J. Newman, D.K. Newman, and D.D. Gutterman. 2006. Peroxynitrite reduces the endothelium derived hyperpolarizing factor component of coronary flow-mediated dilation in PECAM-1-knock out mice. American Journal of Physiology: Heart and Circulatory Physiology 290:R57-65.
    • Rathore, V.B., P.J. Newman and D.K. Newman. 2007. Paxillin family members function as Csk binding proteins that regulate Lyn activity in human and murine platelets. Biochemical Journal 403:275-81.
    • Machida, K., C.M. Thompson, K. Dierck, K. Jablonowski, S. Karkkainen, B. Liu, H. Zhang, P.D. Nash, D.K. Newman, P. Nollau, T. Pawson, G.H. Renkema, K. Saksela, M. Schiller, D.-G. Shin and B.J. Mayer. 2007. High-throughput phosphotyrosine profiling using SH2 domains. Molecular Cell26:899-915.
    • Goel, R., B. Boylan, L. Gruman, P.J. Newman, P. North and D.K. Newman. 2007. The proinflammatory phenotype of PECAM-1-deficient mice results in atherogenic diet-induced steatohepatitis. American Journal of Physiology: Gastrointestinal and Liver Physiology 293:G1205-14.
    • Bergom, C., C. Paddock, C. Gao, T. Holyst, D.K. Newman, and P.J. Newman. 2007. An alternatively spliced isoform of PECAM-1 is expressed at high levels in human and murine tissues, and suggests a novel role for the C-terminus of PECAM-1 in cytoprotective signaling. 2008. .J Cell Sci. 121:1235-42.
    • Goel, R., B. Schrank, S. Arora, B. Boylan, B. Fleming, H. Miura, P.J. Newman, R.C. Molthen, and D.K. Newman. 2008. PECAM-1 deficiency affects atherosclerosis in LDL receptor-deficient mice in a site-specific manner. Arterioscler. Thromb. Vasc. Biol. 28:1996-2002.
    • Boylan, B., C. Gao, V. Rathore, J.C. Gill, D.K. Newman and P.J. Newman. 2008. Identification of FcγRIIa as the ITAM-bearing receptor mediating αIIbβ3 outside-in integrin signaling in human platelets. Blood 112:2780-2786.
    • Gao, C., B. Boylan, D. Bougie, J.C. Gill, J. Birenbaum, D.K. Newman, R.H. Aster and P.J. Newman. 2009. Eptifibatide-induced thrombocytopenia and thrombosis in humans require FcγRIIa and the integrin β3 cytoplasmic domain. J. Clin. Invest. 113:504-11.
    • Newman, D.K. 2009. The Y's that bind: Negative regulators of Src family kinase activity in platelets. J. Thromb. Haemost. 7 (Suppl 1) 195-9.
    • Newman, D.K. 2009. PI3Kβ goes to the head of its class. Blood 114:2011-2.
    • Privratsky, J.R., B.E. Tourdot, D.K. Newman and P.J. Newman. 2010. The anti-inflammatory actions of PECAM-1 do not involve regulation of endothelial cell NF-κB. J. Immunol. 184:3157-63.
    • Bayat, B., S. Werth, U.J.H. Sachs, D.K. Newman, P.J. Newman, and S. Santoso. 2010. Neutrophil transmigration mediated by the neutrophil-specific antigen CD177 is influenced by the endothelial S536N dimorphism of PECAM-1. J. Immunol. 184:3889-93.
    • Fornasa, G., E. Groyer, M. Clement, J. Dimitrov, C. Compain, A.-T. Gaston, A. Varthaman, J. Khallou-Laschet, D. K. Newman, S. Graff-Dubois, A. Nicoletti, and G. Caligiuri. 2010. TCR stimulation drives cleavage and shedding of the ITIM-receptor CD31. J. Immunol. 184:5485-92.
    • Crockett, J., D.K. Newman, and P.J. Newman. PECAM-1 is a negative regulatory of laminin-induced platelet activation. J. Thromb. Haemost. 8:1584-93.
    • Privratsky, J.R., D. K. Newman, and P.J. Newman. PECAM-1: Conflicts of interest in inflammation. Life Sciences 87:69-82.
    • Keane, C., H. Peterson, Reynolds, K., D.K. Newman, D. Cox, H.F. Jenkinson, P.J. Newman and S.W. Kerrigan. 2010. Contribution of outside-in αIIbβ3-mediated activation of human platelets by the colonizing bacterium, Streptococcus gordonii, to the thrombotic complications of infective endocarditis. Arterioscler. Thromb. Vasc. Biol. 30:2408-15.
    • Moraes, L.A., L.M. Holbrook, C.I. Jones, N.E. Barrett, M. Spyridon, T. Sage, D.K. Newman, and J.M. Gibbins. 2010. PECAM-1 regulates platelet function through the modulation of the GAB1-SHP-2-PI3-kinase signalling complex. J. Thromb. Haemost. 8:2530-41.
    • McCormick, M.E., R. Goel, D. Fulton, S. Oess, D. Newman, and E. Tzima. 2011. Platelet-Endothelial Cell Adhesion Molecule-1 regulates endothelial NO synthase activity and localization through signal transducers and activators of transcription 3 dependent NOSTRIN expression. Arterioscler. Thromb. Vasc. Biol. 31:643-9.
    • Ming, Z., Y. Hu, J. Xiang, Polewski, P.J. Newman, and D.K. Newman. 2011. Lyn and PECAM-1: Interdependent inhibitors of platelet responsiveness. Blood 117:3903-6.
    • Privratsky, J.R., C.M. Paddock, O. Florey, D.K. Newman, W.A. Muller, and P.J. Newman. 2011. Relative contribution of PECAM-1 adhesion and signaling to the maintenance of vascular integrity. J. Cell. Sci. 124:1477-85.
    • Gao, C., B. Boylan, J. Fang, D.A. Wilcox, D.K. Newman, and P.J. Newman. 2011. Heparin promotes platelet responsiveness by potentiating αIIbβ3-mediated outside-in signaling. Blood 117:4946-52.
    • Paddock, C., B.L. Lytle, F.C. Peterson, T. Holyst, P.J. Newman, B.F. Volkman, and D.K. Newman. 2011. Residues within a lipid-associated segment of the PECAM-1 cytoplasmic domain are susceptible to inducible, sequential phosphorylation. Blood 117:6012-23.
    • Privratsky, J.R., S.B. Tilkens, D.K. Newman, and P.J. Newman.  2012.  PECAM-1 dampens cytokine levels during LPS-induced endotoxemia by regulating leukocyte trafficking.  Life Sciences 90:177-84.
    • Ma, P., A. Cierniewska, R. Signarvic, M. Cieslak, H. Kong, A.J. Sinnamon, R.R. Neubig, D.K. Newman, T.J. Stalker, and L.F. Brass.  2012.  A newly-identified complex of spinophilin and the tyrosine phosphate, SHP-1, modulates platelet activation by regulating the binding of RGS proteins to spinophilin.  Blood 119:1935-45.
    • Dunne, E., C.M. Spring, A. Rehemann, W. Jin, M.C. Berndt, D.K. Newman, P.J. Newman, H. Ni, and D. Kenny.  2012.  Cadherin 6 has a functional role in platelet aggregation and thrombus formation.  Arerioscler. Thromb. Vasc. Biol. 32:1724-31.
    • Zhi, H., L. Rauova, V. Hayes, C. Gao, B. Boylan, D.K. Newman, S.E. McKenzie, B.C. Cooley, M. Poncz, and P.J. Newman.  2013.  Cooperative integrin/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo.  Blood 121:1858-67.
    • Zheng, Y., M. Yu, A. Podd, L. Yuan, D.K.Newman, R. Wen, G. Apperally, and D. Wang.  2013. Critical role for marginal zone B cells in PF4/heparin antibody production.  Blood 121:3484-92.
    • Tourdot, B.E., M. Brenner, K. Keough, T. Holyst, P.J. Newman, and D.K. Newman.  2013.  Immunoreceptor tyrosine-based inhibitory motif (ITIM)-mediated inhibitory signaling is regulated by sequential phosphorylation mediated by distinct nonreceptor tyrosine kinases: A case study involving PECAM-1.  Biochemistry 184:3157-63.
    • Zheng, Y., A.W. Wang, M. Yu, A. Padmanabhan, B.E. Tourdot, D.K. Newman, G.C. White, R.H. Aster, R. Wen, and D. Wang.  2014.  Role of B cell tolerance in regulating production of antibodies causing heparin-induced thrombocytopenia.  Blood 123:931-4.
    • Clement, M., G. Fornasa, S. Loyau, M. Morvan, P. Larghi, D. Le Roux, K. Guedj, F. Andreata, J. Khallou-Laschet, G. Bismuth, G. Chiocchia, C. Hivroz, D.K. Newman, A. Nicoletti, and G. Caligiuri. 2015. Upholding the T cell immune-regulatory function of CD31 inhibits the formation of T/B immunological synapses in vitro and attenuates the development of experimental autoimmune arthritis in vivo. Journal of Autoimmunity 56:23-33.
    • Zheng, Y., T. Adams, H. Zhi, M. Yu, R. Wen, P.J. Newman, D. Wang and D.K. Newman. 2015. Restoration of responsiveness of PLCγ2-deficient platelets by enforced expression of PLCγ1. PLoS One 10(3):e0119739 (PMCID: PMC4368822).
    • Zhi, H., N. Wu, J. Dai, P. Liu, H. Hu, J. Zhu, D.K. Newman, C. Gao and P.J. Newman. 2015. Platelet activation and thrombus formation over IgG immune complexes requires integrin αIIbβ3 and Lyn kinase. PLoS One 10(8):e0135738 (PMCID: PMC4546160).
    • Newman, D.K.  2015.  CLEC-2: The Inside Story. Blood 125:3972-4.
    • Brenner, M.K., S. Clarke, D.K. Mahnke, R.S. Bercovitz, A. Tomita-Mitchell, M.E. Mitchell and D.K. Newman.  2016.  Effect of 22q11.2 deletion on bleeding and transfusion utilization in children with congenital heart disease undergoing cardiac surgery.  Pediatric Research 79(2):318-24.
    • Newman, D.K., G. Fu, T. Adams, W. Cui, V. Arumugam, T. Bluemn, and M.J. Riese. 2016.  The adhesion molecule PECAM-1 enhances the TGFb-mediated inhibition of T cell function.  Science Signaling 9(418):ra27 (PMCID: PMC5087802).
    • Bercovitz, R.S., M.K. Brenner, and D.K. Newman.  2016.  A whole blood model of thrombocytopenia that controls platelet count and hematocrit.  Annals of Hematology 95(11):1887-94.
    • Lertkiatmongkol, P, C Paddock, DK Newman, J Zhu, MJ Thomas, and PJ Newman. 2016.  The role of sialylated glycans in human PECAM-1-mediated trans-homophilic interactions and endothelial cell barrier function.  Journal of Biological Chemistry 291(50):26216-25 (PMCID: PMC5207088).
    • Fu, G., M. Yu, Y. Chen, Y. Zheng, W. Zhu, D. Newman, D. Wang, and R. Wen.  2017.  Phospholipase Cγ1 (PLCγ1) is essential for pre-TCR signal transduction and pre-T cell development. European Journal of Immunology 47(1):74-83.
    • Liao, D., H. Mei, Y. Hu, D.K. Newman and P.J. Newman.  2018.  CRISPR-mediated deletion of the PECAM-1 cytoplasmic domain increases receptor lateral mobility and strengthens endothelial cell junctional integrity.  Life Sciences 193:186-93.
    • Bercovitz, R.S., A.C. Shewmake, D.K. Newman, R.A. Niebler, J.P. Scott, E.A. Stuth,  P. Simpson, K. Yan, and R.K. Woods. 2018.  A universal definition of excessive postoperative bleeding in infants undergoing cardiac surgery with cardiopulmonary bypass.  The Journal of Thoracic and Cardiovascular Surgery 155(5):2112-24.
    • Scott, J.P., R.A. Niebler, E.A.E. Stuth, D.K. Newman, J.S. Tweddell, R.S. Bercovitz, D.W. Benson, R. Cole , P.M. Simpson, K.Yan, and R.K. Woods.  2018.  Rotational Thromboelastometry Rapidly Predicts Thrombocytopenia and Hypofibrinogenemia during Neonatal Cardiopulmonary Bypass.  World Journal for Pediatric and Congenital Heart Surgery 9(4):424-33.
    • Wesley, E., G. Xin, D. McAllister, S. Malarkannan, D.K. Newman, M.B. Dwinell, W. Cui, B.D. Johnson, and M.J. Riese.  2018.  Diacylglycerol kinase ζ (DGKζ) and Casitas b-lineage proto-oncogene b-deficient mice have similar functional outcomes in T cells but DGKζ-deficient mice have increased T cell activation and tumor clearance.  Immunohorizons 2(4):107-18 (PMCID: PMC6048965).
    • Newman, D.K., G. Fu, L. McOlash, D. Schauder, P.J. Newman, W. Cui, S. Rao, B.D. Johnson, J.A. Gershan, and M.J. Riese.  PECAM-1 (CD31) expression in na├»ve and memory, but not acutely activated, CD8+ T cells. Journal of Leukocyte Biology 104(5):883-93
    • Newman, D.K.  2018.  G6b-B:  The “Y’s” and Wherefores.  Blood (In Press).
    • Zwifelhofer, N.M., R.S. Bercovitz, L.A. Weik, A. Moroi, S. LaRose, P.J. Newman and D.K. Newman.  2019.  Hemizygosity for the gene encoding glycoprotein Ib beta (GPIBβ) is not responsible for macrothrombocytopenia and bleeding in patients with 22q11.2 deletion syndrome.  Journal of Thrombosis and Haemostasis 17(2):295-305 (PMCID: PMC6410711 – Available 02-01-2020).
    • Moroi, A., N. Johnson, M.J. Riese, D.K. Newman and P.J. Newman.  2019.  Diacylglycerol kinase zeta (DGKζ) is a negative regulator of GPVI-mediated platelet activation.  Blood Advances 3(7):1154
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