Peter J. Newman, PhD
Peter J. Newman, PhD
Jacquelyn Fredrick Endowed Chair for Foundational Research, Senior Investigator
Jacquelyn Fredrick Endowed Chair for Foundational Research
Versiti Blood Research Institute
Departments of Pharmacology and Toxicology and Cell Biology, Neurobiology and Anatomy
Medical College of Wisconsin
Education and training
St. Louis University, PhD, 1983
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 and the generation of antigenically-distinct megakaryocytes and platelets from induced pluripotent stem (iPS) cells, and the use of a novel humanized mouse to examine the pathophysiology of platelet alloimmune disorders. 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:
- 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.
- Examine the structural and functional basis of allosteric regulation of PECAM-1 homophilic binding affinity.
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 fetal/neonatal alloimmune thrombocytopenia (FNAIT). FNAIT 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:
- Exploiting recent advances in CRISPR/Cas9 gene editing technology to:
- generate megakaryocyte progenitor cells, megakaryocytes, and platelets from induced pluripotent stem (iPS) cells to create platelet alloantigen-specific cell lines capable of long-term self-renewal, cryopreservation, and distribution.
- Modifying genes encoding strategically selected cytosolic signaling molecules with the goal of improving the function and hemostatic effectiveness of iPSC-derived platelets and megakaryocytes.
- Using a recently developed novel humanized mouse model to conduct preclinical studies designed to evaluate th effectiveness of novel therapeutics to prevent or treat FNAIT.
- 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
Huiying Zhi, MD
Research Scientist II
Nanyan Zhang, MD, PhD
Research Scientist II
Jesse Sundlov, PhD
Senior Research Technologist
Alyssa Moroi, PhD
Research Scientist I
Assistant Research Technologist
- 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
- 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
- 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.
- 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
- 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 deglycosylated 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
- 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 conversion 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
- 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
- Zhi H, MT Ahlen, AM Thinn, P Lertkiatmongkol, B Curtis, B Skogen, J Zhu, and PJ Newman: High-resolution mapping of the polyclonal immune response to the human platelet alloantigen, HPA-1a: Implications for diagnosis, prophylaxis and treatment. Blood Advances 2(21):3001-3011, 2018. PMCID: PMC6234362
- Zhang N and PJ Newman: Packaging functionally important plasma proteins into the α-granules of human induced pluripotent stem cell-derived megakaryocytes. J Tissue Eng Regen Med 13(2):244-252, 2019. PMCID: PMC6742440
- Moroi AJ, N Zwifelhofer, MJ Riese, DK Newman and PJ Newman: Diacylglycerol kinase zeta (DGKζ) is a negative regulator of GPVI-mediated platelet activation. Blood Advances 3:1154-1166, 2019. PMCID: PMC6457232
- Zhang N, S Santoso, RH Aster, BR Curtis, and PJ Newman: Bioengineered iPSC-derived megakaryocytes for the detection of platelet-specific patient alloantibodies. Blood 134:e1-e8, 2019. PMCID: PMC6887112 (with Inside Blood commentary 134:1887-1888)
- Zhi H, T Kanaji, G Fu, DK Newman, and PJ Newman: Generation of PECAM-1 (CD31) conditional knockout mice. Genesis 2020 58:e23346. doi.org/10.1002/dvg.23346. PMCID: PMC7021573
- Zhi H, MT Ahlen, B Skogen, DK Newman, and PJ Newman: Preclinical evaluation of immunotherapeutic regimens for fetal/neonatal alloimmune thrombocytopenia. Blood Advances 2021 (in press).
- Polymorphism of human platelet membrane glycoprotein IIIa and diagnostic and therapeutic applications thereof. Filed 04/27/1989 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 12/01/1989 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 01/19/1990 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 07/01/1991 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).
- Polymorphism of human platelet membrane glycoprotein IIIa and diagnostic and therapeutic applications thereof. Filed 11/22/1991. 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 06/30/1993. 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 07/05/1994. 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 10/07/1994. 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 02/21/1995 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 06/07/1995 U.S. patent application number 08/478,210. 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 07/01/1991. U.S. patent serial number 721,321. 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 11/16/1994. US patent serial number 08/341,300. Issued February 1, 2000 as U.S. patent number 6,020,188.
- Therapeutic use of Platelet Endothelial Cell Adhesion Molecule-1 Compositions. Filed 06/07/1995. U.S. patent application number 08/478,208. 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 11/05/2014 as US Provisional Application 62/074,870, and on 11/03/15 as US Patent 14/931,321. Issued July 28, 2020 as U.S. patent number 10,725,041.
- A murine model of fetal/neonatal alloimmune thrombocytopenia. Filed 11/05/2019 as US Patent Application 16/674,804 (patent pending).
- A method to bioengineer Designer Red Blood Cells using gene editing and stem cell methodologies. Filed 06/26/2020 as a U.S. Patent Application No. 16/913,741 (patent pending).