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Peter J. Newman, PhD

Peter J. Newman, PhD

Vice President for Research

Associate Director
Versiti Blood Research Institute

Professor
Department of Pharmacology
Department of Cell Biology, Neurobiology, and Anatomy
Medical College of Wisconsin

Education and training

Doctoral Training
St. Louis University, PhD, 1983

Contact Us

Peter J. Newman, PhD

Vice President for Research
Email (414) 937-6237 Fax: (414) 937-6284

  • Research Interests

    Thrombosis, Hemostasis and Vascular Biology

    Our laboratory divides its attention between exploring the structure and function of PECAM-1 in the blood and vascular cells in which it is expressed (funded through a long-standing R01) and the generation of antigenically-distinct megakaryocytes and platelets from induced pluripotent stem (iPS) cells (funded through a Program Project grant from the NHLBI). Techniques range from CRISPR-mediated gene editing to protein crystallography to the development of animal models of platelet alloimmunity.

    The Biology of PECAM-1: PECAM-1 (also known as CD31) is a cellular adhesion and signaling receptor comprised of six extracellular immunoglobulin (Ig) - like homology domains, a short transmembrane domain, and a 118 amino acid cytoplasmic domain that becomes serine and tyrosine phosphorylated upon cellular activation. PECAM-1 expression is restricted to blood and vascular cells. In circulating platelets and leukocytes, PECAM-1 functions largely as an inhibitory receptor that, via regulated sequential phosphorylation of its cytoplasmic domain, limits cellular activation responses. PECAM-1 is also highly expressed at endothelial cell intercellular junctions, where it functions as a mechanosensor, as a regulator of leukocyte trafficking, and in the maintenance of endothelial cell junctional integrity. PECAM-1–PECAM-1 homophilic interactions mediated by N-terminal Ig domain 1 are required for border localization, and contribute importantly to steady-state endothelial cell barrier stability and to recovery of endothelial cell junctional integrity, both in vitro and in vivo, following inflammatory or hemostatic challenge. Current studies seek to:

    1. Build on recent crystallographic data of the PECAM-1 homophilic binding domain to define the molecular and structural determinants of PECAM-1-mediated cellular interactions. 
    2. Examine the structural and functional basis of allosteric regulation of PECAM-1 homophilic binding affinity
    3. Identify serine/threonine kinase(s) that trigger PECAM-1-mediated inhibitory signaling
    4. Investigate the role of carbohydrate residues in PECAM-1/PECAM-1 homophilic interactions
       

    Generation of alloantigen-specific “Designer Platelets” in mice and man for diagnostic and investigative use: Immune reactions to platelets, initiated either by transfusion or by pregnancy, are responsible for two serious immunopathogenic syndromes: Post-transfusion purpura and neonatal alloimmune thrombocytopenia (NAIT). NAIT is caused by maternal antibodies generated in response to paternally-inherited antigens present on fetal platelets that re-cross the placenta and bind to fetal and/or neonatal platelets, resulting in thrombocytopenia often serious enough to require transfusion, and in the most severe cases causing intracranial hemorrhage and intrauterine death. To develop a greater understanding of the etiology of platelet alloimmune disorders, and to develop novel reagents leading to greatly improved diagnostic testing, we are:
     

    1. Exploiting recent advances in CRISPR gene editing technology to generate megakaryocyte progenitor cells, megakaryocytes, and platelets from induced pluripotent stem cells to establish a novel platform for the field of Transfusion Medicine – namely the creation of platelet alloantigen-specific cell lines capable of long-term self-renewal, cryopreservation, and distribution. 
    2. Using CRISPR technology to develop a novel humanized mouse model of NAIT that will allow us to resolve outstanding issues in platelet alloimmunity. 
  • Grant Support

    Grants

    • NIH R35 Outstanding Investigator Award (OIA) HL139937 (3/1/2018 - 2/28/2025) Basic Investigation and Translational Applications Concerning the Cell and Molecular Biology of Blood and Vascular Cells 
    • NIH Postdoctoral Training Grant T32 HL007209 (Co-PI with GC White) (07/01/1976 - 11/30/2019) Research Training in Transfusion Medicine

    Ongoing NIH-Funded Research Projects

    • Role of PECAM-1 adhesion and signaling in endothelial cell barrier function and vascular permeability
    • The role of carbohydrate residues in PECAM-1-mediated homophilic binding interactions
    • Identification of serine/threonine kinase(s) that trigger PECAM-1-mediated inhibitory signaling
    • Crystallographic studies of PECAM-1-mediated homophilic interactions.
    • Exploiting recent advances in CRISPR gene editing technology to generate antigenically-distinct megakaryocyte progenitor cells, megakaryocytes, and platelets from induced pluripotent stem cells
    • Using CRISPR technology to develop a novel humanized mouse model of NAIT that will allow us to resolve outstanding issues in platelet alloimmunity.
  • Lab

    Huiying Zhi, MD
    Research Scientist II

     Nanyan Zhang, MD, PhD
    Research Scientist II

    Jesse Sundlov, PhD
    Postdoctoral Fellow

    Cathy Paddock 
    Senior Research Technologist

    Alyssa Moroi, PhD
    Research Scientist I

    Kathryn Williams
    Assistant Research Technologist

  • Publications
    • Baldassare JJ, RA Kahn, MA Knipp, and PJ Newman: Reconstitution of platelet proteins into phospholipid vesicles: Functional proteoliposomes. J Clin Invest 1985, 75:35-39.
    • Newman PJ, J Gorski, GC White II, S Gidwitz, CJ Cretney, and RH Aster: Enzymatic amplification of platelet-specific messenger RNA using the polymerase chain reaction. J. Clin. Invest 1988, 82:739-743.
    • Newman PJ, R Derbes, and RH Aster: The human platelet alloantigens, PlA1 and PlA2, are associated with a Leucine33/Proline33 amino acid polymorphism in membrane glycoprotein IIIa, and are distinguishable by DNA typing. J Clin Invest 1989, 83:1778-1781.
    • Newman PJ, MC Berndt, J Gorski, GC White II, SL Lyman, C Paddock, and WA Muller: PECAM-1 (CD31): Cloning and relation to adhesion molecules of the immunoglobulin gene superfamily. Science 1990, 247:1219-1222.
    • Newman PJ, U Seligsohn, S Lyman, M Poncz, and BS Coller: The molecular genetic basis of Glanzmann's thrombasthenia in the Iraqi-Jewish and Arab populations in Israel. Proc Natl Acad Sci (USA) 1991, 88:3160-3164.
    • Jackson DE, CM Ward, R Wang, and PJ Newman: The protein tyrosine phosphatase SHP-2 binds Platelet/Endothelial Cell Adhesion Molecule-1 (PECAM-1) and forms a distinct signaling complex during platelet aggregation: Evidence for a mechanistic link between PECAM-1 and integrin-mediated signal transduction. J. Biol Chem 272:6986-6993, 1997.
    • Wang R, SJ Shattil, DR Ambruso, and PJ Newman: Truncation of the cytoplasmic domain of β3 in a variant form of Glanzmann thrombasthenia abrogates signaling through the αIIbβ3 complex. J Clin Invest 100:2393-2403, 1997.
    • 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. PMID: 11238114
    • 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. Blood102:169-179, 2003. PMID: 12649141
    • 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/FcRγ-chain complex from the human platelet surface. Blood 104:1350-1355, 2004. PMID: 15150079
    • 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. PMID: 15319204
    • 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 vivoeffectiveness 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
    • 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, 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.
    • Paddock, CA, B Lytle, F Peterson, T Holyst, PJ Newman, B Volkman, and DK Newman. Residues within a lipid-associated segment of hte PECAM-1 cytoplasmic domain are susceptible to inducible, sequential phosphorylation. Blood 117:6012-6023, 2011.
    • Kanaji T, J Ware, T Okamura, and PJ Newman: GPIbα regulates platelet size by controlling the subcellular localization of filamin. Blood 119:2906-2913, 2012. (With Inside Blood commentary: 119:2702-2703 and Journal cover photo). PMCID:PMC3327465
    • Kuckleburg C and PJ Newman: Neutrophil proteinase 3 (PR3) acts on protease-activated receptor-2 to enhance vascular endothelial cell barrier function. Arterioscler Thromb Vasc Biol 33:275-284, 2013. PMCID:PMC3562705
    • Zhi H, L Rauova, V Hayes, J Crockett, C Gao, B Boylan, DK Newman, SE McKenzie, BC Cooley, M Poncz, and PJ Newman: Cooperative integrin/ITAM signaling in platelets enhances thrombus formation in vitro and in vivo. Blood 121:1858-1867, 2013. (with Inside Blood commentary: 121:1674-1675 and Journal cover photo). PMCID:PMC3591804
    • Bakchoul T, A Greinacher, UJ Sachs, A Krautwurst, H Renz, H Harb, G Bein, PJ Newman, and S Santoso: Inhibition of HPA-1a alloantibody-mediated platelet destruction by a degly-cosylated anti-HPA-1a monoclonal antibody: towards targeted treatment of fetal-alloimmune thrombocytopenia. Blood 122:321-327, 2013 (Plenary Paper with Inside Blood commentary: 122:307-309). PMCID:PMC3716199
    • Kanaji T, S Kanaji, RR Montgomery, SB Patel, and PJ Newman: Platelet hyperreactivity explains the bleeding abnormality and macrothrombocytopenia in a murine model of sitosterolemia. Blood 122:2732-2742, 2013. (with Inside Blood commentary 122:2534-2535) PMCID: PMC3795464
    • Mei H, JM Campbell, CM Paddock, P Lertkiatmongkol, MW Mosesson, R Albrecht, and PJ Newman: Regulation of endothelial cell barrier function by antibody-driven affinity modulation of Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1). J Biol Chem 289: 20836-20844, 2014. PMCID: PMC4110291
    • Zhang N, H Zhi, S Rao and PJ Newman: Designer platelets: CRISPR/Cas-mediated conver-sion of human platelet alloantigen allotypes. Blood 127:675-680, 2016. (Plenary Paper with Inside Blood commentary: 127:665-666). PMCID: PMC4751021
    • Paddock C, D Zhou, P Lertkiatmongkol, PJ Newman, and J Zhu. Structural basis for PECAM-1 homophilic binding. Blood 127:1052-1061, 2016. PMCID: PMC4768429
    • Santoso S, H Wihadmadyatami, T Bakchoul, S Werth, N Al-Fakhri, G Bein, V Kiefel, J Zhu, PJ Newman, B Bayat, and UJ Sachs. Anti-endothelial αvβ3 antibodies are a major cause of intracranial bleeding in fetal/neonatal alloimmune thrombocytopenia. Arterioscler Thromb Vasc Biol 36:1517-1524, 2016. PMCID: PMC5140275
    • Dai B, P Wu, F Xue, R Yang, Z Yu, K Dai, C Ruan, G Liu, PJ Newman, and C Gao: Integrin-αIIbβ3-mediated outside-in signaling activates a negative feedback pathway to suppress platelet activation Thrombosis and Haemostasis 116:918-930, 2016. PMID:27465472
    • Lertkiatmongkol P, C Paddock, DK Newman, J Zhu, MJ Thomas, and PJ Newman: The role of sialylated glycans in human Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1)-mediated trans homophilic interactions and endothelial cell barrier function. J Biol Chem 291:26216-26225, 2016. PMCID: PMC5207088.
    • Liao D, H Mei, Y Hu, DK Newman, and PJ Newman: CRISPR-mediated deletion of the PECAM-1 cytoplasmic domain increases receptor lateral mobility and strengthens endothelial cell junctional integrity. Life Sciences 193:186-193, 2018. PMCID:PMC5754039
  • Other

    Patents

    • Polymorphism of human platelet membrane glycoprotein IIIa and diagnostic and therapeutic applications thereof. Filed 4/27/89 U.S. patent serial number 343,827. Japan patent application number 506,829. European PCT application number PCT-US90-02104. Issued February 25, 1992 as U.S. patent number 5,091,302.
    • Polymorphism of human platelet membrane glycoprotein IIb and diagnostic and therapeutic applications thereof. Filed 12/01/89 U.S. patent serial number 433,946. Issued July 25, 1995 as U.S. patent number 5,436,163.
    • Platelet cell adhesion molecule and variants thereof. Filed 01/19/90 U.S. patent serial number 466,140. European PCT application number PCT-US90-07418. Australian patent application number 71546/91. Japanese patent application number 32275/90. Issued November 23, 1993 as U.S. Patent Number 5,264,554.
    • Polynucleotides for determining the Pen polymorphism of human platelet membrane. Filed 07/1/91 U.S. patent serial number 08/482,174. Issued July 14, 1998 as U.S. patent number 5,780,229. European PCT application number PCT-92914287.5 (0593572). Notice of allowance in Europe received 4/24/97. U.S. divisional (149 case) covering methods and kits is pending.
    • Polymorphism of human platelet membrane glycoprotein IIIa and diagnostic and therapeutic applications thereof. Filed 11/22/91. Divisional application covering non-human antibodies to PlA1 and PlA2 alloantigenic determinants. U.S. patent serial number 797,117. Issued February 21, 1995 as U.S. patent number 5,391,714.
    • Molecular basis of the human platelet Bra/Brb alloantigen system and applications thereof. Filed 6/30/93. U.S. patent serial number 86,634. Issued May 14, 1996 as U.S. patent number 5,516,634.
    • Platelet-Endothelial Cell Adhesion Molecule-1 promoters and uses thereof. Filed 7/5/94. Patent covering the human PECAM-1 promoter and vectors that use it to drive transcription. U.S. patent serial number 08/270,985. European PCT application filed July 5, 1995. Issued September 16, 1997 as U.S. patent number 5,668,012.
    • Nucleic acids for the detection of the Bak polymorphism in human platelet membrane glycoprotein IIb. Filed 10/7/94. U.S. patent serial number 319,946. Issued July 29, 1997 as U.S. patent number 5,652,357.
    • Polymorphism of human platelet membrane glycoprotein IIIa and diagnostic and therapeutic applications thereof. Filed 2/21/95 Divisional application covering oligonucleotides to detect the PlA1 and PlA2 alleles of GPIIIa, and peptides used to make PIA - specific atnibodies. U.S. patent serial number 392,363. Issued September 23, 1997 as U.S. patent number 5,670,337
    • Platelet cell adhesion molecule and variants thereof. Filed 06/07/95.U.S. patent application number 08/478,210. One claim covering sense and anti-sense oligonucleotide probes to any region of PECAM-1 cDNA. Issued June 29, 1999 as U.S. patent number 5,917,030.
    • Methods and kits for determining the Pen polymorphism of human platelet membrane glycoprotein IIIa. Filed 07/01/91. U.S. patent serial number 721,321. Twenty-seven claims covering DNA typing and non-human antibody-based tying for the Pena and Penb epitopes on GPIIIa. Issued October 26, 1999 as U.S. patent number 5,972,601.
    • Polynucleotides encoding Platelet Endothelial Cell Adhesion Molecule (PECAM-1) and fragments thereof. Filed 11/16/94. US patent serial number 08/341,300. Ten claims covering cDNAs encoding full-length PECAM-1, the extracellular domain of PECAM-1, and subsets thereof. Issued February 1, 2000 as U.S. patent number 6,020,188.
    • Therapeutic use of Platelet Endothelial Cell Adhesion Molecule-1 Compositions. Filed 06/07/95. U.S. patent application number 08/478,208. Twelve claims covering methods for using soluble PECAM-1 to modulate angiogenesis, relieve inflammation, and inhibit arterial occlusions associated with atherosclerosis or vascular trauma. Issued July 11, 2000 as U.S. patent number 6,087,331.
    • Method to Bioengineer Designer Platelets using CRISPR/Cas9 and Stem Cell Methodologies. Filed 11/05/14 as US Provisional Application 62/074,870.
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