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Peter N. Walsh, MD, PhD

 

Peter N. Walsh, MD, PhD

 

Professor Emeritus, Medicine

Professor, Sol Sherry Thrombosis Research Center

Professor, Fels Institute for Cancer Research and Molecular Biology

Professor, Biochemistry

Telephone:  215-707-4375

Fax:  215-707-3005

Email: pnw@temple.edu

 

Sol Sherry Thrombosis Research Center

Fels Institute of Cancer Research and Molecular Biology

Department of Biochemistry

 

Educational Background:

 

Amherst College, Amherst, MA

1953-1957, A.B., Pre-Medicine

 

Washington University School of Medicine, St. Louis, MO

1957-1961, M.D., Medicine

 

Barnes Hospital, St. Louis, MO

1961-1962, Medicine Intern

1962-1963, Assistant Resident

 

Washington University School of Medicine, St. Louis, MO

1963-1964, Medicine Fellow (Hematology)

 

Palo Alto-Stanford Hospital, Palo Alto, CA

1964-1965, Senior Resident in Medicine

 

Barnes Hospital, St. Louis, MO

1965-1966, Chief Resident in Medicine

 

Medical Liaison Officer

National Institutes of Health, Bethesda, MD

1966-1969, Urokinase Pulmonary Embolism Trial

 

University of Oxford, Oxford, England

1972, D.Phil., Bio-Med. Sciences

 

Oxford Haemophilia Centre, Churchill Hospital, England

1969-1972, Research Fellow in Blood Coagulation

(NIH Special Postdoctoral Research Fellowship)

 

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Research Interests:

 

Molecular and Cellular Interactions of Blood Coagulation Factor XI.
NIH-funded research focuses on the characterization, intermolecular interactions and structure-function relationships of coagulation proteins, including Factor XI.


Molecular Interactions of Factor XI.

Recent observations resulting in the recognition of the essential role of FXI in hemostasis concern the relationship of its domain structure to its biological function, the molecular genetics of FXI, its molecular and cellular interactions, the elucidation of newly discovered pathways for activation of FXI, and the expression and regulation of its enzymatic activity. The long-term goals of this project are to elucidate the molecular mechanisms involved in the interaction of FXI with protein and cell surface ligands involved in its activation and in the expression and regulation of FXIa enzymatic activity.


Exosite Function in the Catalytic Domain of Coagulation Factor XIa.

The long-term goals of this project are to elucidate the molecular mechanisms involved in the interaction of FXIa with its substrate, its cellular (platelet) receptor(s) and its regulators, including the platelet-secreted Kunitz inhibitor, protease nexin-2 and to define the structural biology mediating the exposure of exosites within the catalytic domain that result from the conversion of the zymogen to the protease.


Antithrombotic Effects of FXIa Inhibition by the KPI Domain of PN2.

The goals of this project are to determine the mechanism by which the kunitz protease inhibitor (KPI) domain of protease nexin-2 (PN2) prevents thrombosis and stroke in mice; to study mutant forms of KPI with increased antifibrinolytic and decreased anticoagulant activity; and to develop antithrombotic gene therapy using KPI. The ultimate goal of the proposed work is to develop a new class of anticoagulants to provide safe and effective treatment and prophylaxis of diseases characterized by excessive blood clotting.

 

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PUBMED PUBLICATIONS :


Recent Medically Related Publications, Obtained from PubMed (Click on PubMed ID to view abstract)

23172304. Navaneetham D, Wu W, Li H, Sinha D, Tuma RF, Walsh PN, P1 and P2' site mutations convert protease nexin-2 from a factor XIa inhibitor to a plasmin inhibitor. J Biochem 153:2(221-31)2013 Feb

22674803. Wu W, Li H, Navaneetham D, Reichenbach ZW, Tuma RF, Walsh PN, The kunitz protease inhibitor domain of protease nexin-2 inhibits factor XIa and murine carotid artery and middle cerebral artery thrombosis. Blood 120:3(671-7)2012 Jul 19

21778227. Su YC, Miller TN, Navaneetham D, Schoonmaker RT, Sinha D, Walsh PN, The role of factor XIa (FXIa) catalytic domain exosite residues in substrate catalysis and inhibition by the Kunitz protease inhibitor domain of protease nexin 2. J Biol Chem 286:36(31904-14)2011 Sep 9

20647553. Navaneetham D, Sinha D, Walsh PN, Mechanisms and specificity of factor XIa and trypsin inhibition by protease nexin 2 and basic pancreatic trypsin inhibitor. J Biochem 148:4(467-79)2010 Oct

18441012. Wu W, Sinha D, Shikov S, Yip CK, Walz T, Billings PC, Lear JD, Walsh PN, Factor XI homodimer structure is essential for normal proteolytic activation by factor XIIa, thrombin, and factor XIa. J Biol Chem 283:27(18655-64)2008 Jul 4

18020374. Miller TN, Sinha D, Baird TR, Walsh PN, A catalytic domain exosite (Cys527-Cys542) in factor XIa mediates binding to a site on activated platelets. Biochemistry 46:50(14450-60)2007 Dec 18

17676929. Sinha D, Marcinkiewicz M, Navaneetham D, Walsh PN, Macromolecular substrate-binding exosites on both the heavy and light chains of factor XIa mediate the formation of the Michaelis complex required for factor IX-activation. Biochemistry 46:34(9830-9)2007 Aug 28

17257616. Riley PW, Cheng H, Samuel D, Roder H, Walsh PN, Dimer dissociation and unfolding mechanism of coagulation factor XI apple 4 domain: spectroscopic and mutational analysis. J Mol Biol 367:2(558-73)2007 Mar 23

16752917. London FS, Marcinkiewicz M, Walsh PN, PAR-1-stimulated factor IXa binding to a small platelet subpopulation requires a pronounced and sustained increase of cytoplasmic calcium. Biochemistry 45:23(7289-98)2006 Jun 13

16699514. Papagrigoriou E, McEwan PA, Walsh PN, Emsley J, Crystal structure of the factor XI zymogen reveals a pathway for transactivation. Nat Struct Mol Biol 13:6(557-8)2006 Jun

16229474. Ahmad SS, Walsh PN, Role of the C2 domain of factor VIIIa in the assembly of factor-X activating complex on the platelet membrane. Biochemistry 44:42(13858-65)2005 Oct 25

16085935. Navaneetham D, Jin L, Pandey P, Strickler JE, Babine RE, Abdel-Meguid SS, Walsh PN, Structural and mutational analyses of the molecular interactions between the catalytic domain of factor XIa and the Kunitz protease inhibitor domain of protease nexin 2. J Biol Chem 280:43(36165-75)2005 Oct 28

16042419. Sinha D, Marcinkiewicz M, Lear JD, Walsh PN, Factor XIa dimer in the activation of factor IX. Biochemistry 44:30(10416-22)2005 Aug 2

16042406. Wakabayashi H, Su YC, Ahmad SS, Walsh PN, Fay PJ, A Glu113Ala mutation within a factor VIII Ca2+-binding site enhances cofactor interactions in factor Xase. Biochemistry 44:30(10298-304)2005 Aug 2

15755260. Yang X, Walsh PN, An ordered sequential mechanism for Factor IX and Factor IXa binding to platelet receptors in the assembly of the Factor X-activating complex. Biochem J 390:Pt 1(157-67)2005 Aug 15

15375170. Baglia FA, Shrimpton CN, Emsley J, Kitagawa K, Ruggeri ZM, López JA, Walsh PN, Factor XI interacts with the leucine-rich repeats of glycoprotein Ibalpha on the activated platelet. J Biol Chem 279:47(49323-9)2004 Nov 19

15354267. Walsh PN, Platelet coagulation-protein interactions. Semin Thromb Hemost 30:4(461-71)2004 Aug

15328360. Yang X, Chang YJ, Lin SW, Walsh PN, Identification of residues Asn89, Ile90, and Val107 of the factor IXa second epidermal growth factor domain that are essential for the assembly of the factor X-activating complex on activated platelets. J Biol Chem 279:45(46400-5)2004 Nov 5

15317813. Baglia FA, Gailani D, López JA, Walsh PN, Identification of a binding site for glycoprotein Ibalpha in the Apple 3 domain of factor XI. J Biol Chem 279:44(45470-6)2004 Oct 29

15182201. Sinha D, Badellino KO, Marcinkiewicz M, Walsh PN, Allosteric modification of factor XIa functional activity upon binding to polyanions. Biochemistry 43:23(7593-600)2004 Jun 15

15010476. London FS, Marcinkiewicz M, Walsh PN, A subpopulation of platelets responds to thrombin- or SFLLRN-stimulation with binding sites for factor IXa. J Biol Chem 279:19(19854-9)2004 May 7

14629468. Ahmad SS, London FS, Walsh PN, Binding studies of the enzyme (factor IXa) with the cofactor (factor VIIIa) in the assembly of factor-X activating complex on the activated platelet surface. J Thromb Haemost 1:11(2348-55)2003 Nov

14521588. Walsh PN, Roles of factor XI, platelets and tissue factor-initiated blood coagulation. J Thromb Haemost 1:10(2081-6)2003 Oct

12871539. Ahmad SS, London FS, Walsh PN, The assembly of the factor X-activating complex on activated human platelets. J Thromb Haemost 1:1(48-59)2003 Jan

12663668. Baird TR, Walsh PN, Factor XI, but not prekallikrein, blocks high molecular weight kininogen binding to human umbilical vein endothelial cells. J Biol Chem 278:23(20618-23)2003 Jun 6

12517745. Baglia FA, Shrimpton CN, López JA, Walsh PN, The glycoprotein Ib-IX-V complex mediates localization of factor XI to lipid rafts on the platelet membrane. J Biol Chem 278:24(21744-50)2003 Jun 13

12463164. Walsh PN, Ahmad SS, Proteases in blood clotting. Essays Biochem 38:(95-111)2002

12220193. Ahmad SS, Walsh PN, Coordinate binding studies of the substrate (factor X) with the cofactor (factor VIII) in the assembly of the factor X activating complex on the activated platelet surface. Biochemistry 41:37(11269-76)2002 Sep 17

12167623. Baird TR, Walsh PN, The interaction of factor XIa with activated platelets but not endothelial cells promotes the activation of factor IX in the consolidation phase of blood coagulation. J Biol Chem 277:41(38462-7)2002 Oct 11

12084014. Sinha D, Marcinkiewicz M, Gailani D, Walsh PN, Molecular cloning and biochemical characterization of rabbit factor XI. Biochem J 367:Pt 1(49-56)2002 Oct 1

12029092. Baird TR, Walsh PN, Activated platelets but not endothelial cells participate in the initiation of the consolidation phase of blood coagulation. J Biol Chem 277:32(28498-503)2002 Aug 9

11726655. Wilkinson FH, London FS, Walsh PN, Residues 88-109 of factor IXa are important for assembly of the factor X activating complex. J Biol Chem 277:8(5725-33)2002 Feb 22

11714704. Wilkinson FH, Ahmad SS, Walsh PN, The factor IXa second epidermal growth factor (EGF2) domain mediates platelet binding and assembly of the factor X activating complex. J Biol Chem 277:8(5734-41)2002 Feb 22

11696542. Baglia FA, Badellino KO, Li CQ, Lopez JA, Walsh PN, Factor XI binding to the platelet glycoprotein Ib-IX-V complex promotes factor XI activation by thrombin. J Biol Chem 277:3(1662-8)2002 Jan 18

11487044. Walsh PN, Roles of platelets and factor XI in the initiation of blood coagulation by thrombin. Thromb Haemost 86:1(75-82)2001 Jul

11412111. Badellino KO, Walsh PN, Localization of a heparin binding site in the catalytic domain of factor XIa. Biochemistry 40:25(7569-80)2001 Jun 26

11092900. Dorfman R, Walsh PN, Noncovalent interactions of the Apple 4 domain that mediate coagulation factor XI homodimerization. J Biol Chem 276:9(6429-38)2001 Mar 2

11091186. Shirk RA, Konkle BA, Walsh PN, Nonsense mutation in exon V of the factor XI gene does not abolish platelet factor XI expression. Br J Haematol 111:1(91-5)2000 Oct

10933803. London FS, Walsh PN, Zymogen factor IX potentiates factor IXa-catalyzed factor X activation. Biochemistry 39:32(9850-8)2000 Aug 15

10924522. Baglia FA, Badellino KO, Ho DH, Dasari VR, Walsh PN, A binding site for the kringle II domain of prothrombin in the apple 1 domain of factor XI. J Biol Chem 275:41(31954-62)2000 Oct 13

10823824. Ho DH, Badellino K, Baglia FA, Sun MF, Zhao MM, Gailani D, Walsh PN, The role of high molecular weight kininogen and prothrombin as cofactors in the binding of factor XI A3 domain to the platelet surface. J Biol Chem 275:33(25139-45)2000 Aug 18

10781579. Baglia FA, Walsh PN, Thrombin-mediated feedback activation of factor XI on the activated platelet surface is preferred over contact activation by factor XIIa or factor XIa. J Biol Chem 275:27(20514-9)2000 Jul 7

10777612. Ahmad SS, Scandura JM, Walsh PN, Structural and functional characterization of platelet receptor-mediated factor VIII binding. J Biol Chem 275:17(13071-81)2000 Apr 28

10769134. Badellino KO, Walsh PN, Protease nexin II interactions with coagulation factor XIa are contained within the Kunitz protease inhibitor domain of protease nexin II and the factor XIa catalytic domain. Biochemistry 39:16(4769-77)2000 Apr 25

10630991. Ho DH, Baglia FA, Walsh PN, Factor XI binding to activated platelets is mediated by residues R(250), K(255), F(260), and Q(263) within the apple 3 domain. Biochemistry 39:2(316-23)2000 Jan 18

10605709. Walsh PN, Platelets and factor XI bypass the contact system of blood coagulation. Thromb Haemost 82:2(234-42)1999 Aug

10413468. Wong MY, Gurr JA, Walsh PN, The second epidermal growth factor-like domain of human factor IXa mediates factor IXa binding to platelets and assembly of the factor X activating complex. Biochemistry 38:28(8948-60)1999 Jul 13

9692958. Zhang Y, Ribeiro JM, Guimarães JA, Walsh PN, Nitrophorin-2: a novel mixed-type reversible specific inhibitor of the intrinsic factor-X activating complex. Biochemistry 37:30(10681-90)1998 Jul 28

9632702. Ho DH, Badellino K, Baglia FA, Walsh PN, A binding site for heparin in the apple 3 domain of factor XI. J Biol Chem 273:26(16382-90)1998 Jun 26

9573017. Hu CJ, Baglia FA, Mills DC, Konkle BA, Walsh PN, Tissue-specific expression of functional platelet factor XI is independent of plasma factor XI expression. Blood 91:10(3800-7)1998 May 15

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