Neuenschwander, Pierre, Ph.D.
B.S. Chemistry (ACS), 1985, Rochester Institute of Technology.
Ph.D. Biochemistry & Molecular Biology, 1990, State University of New York at Stony Brook.
- Regulation of factor VIII activation/inactivation by the factor VIIa-tissue factor complex.
- Enzymology of factor IXa, and roles of cofactors.
Blood clotting is necessary for maintaining life. However, certain life-threatening conditions (heart attacks and strokes) can result if clotting is not controlled. Two enzymes involved in clotting are factor VIIa (fVIIa) and factor IXa (fIXa). Both of these enzymes are always present in the circulation, but in an inert form. Clotting ensues only when damage to blood vessels causes a cofactor protein, tissue factor, to be exposed to the circulation thus binding to and "activating" fVIIa. Subsequently, another cofactor protein is also activated (fVIIIa) which binds to and "activates" fIXa. The two resulting enzyme-cofactor complexes (fVIIa-tissue factor and fIXa-fVIIIa) have each been implicated in thrombosis and other clotting diseases. Thus, the purpose of this research program is to characterize both of these "activation" events and elucidate the ability of both of these complexes to regulate clotting.
The long-term goals of my research are to rigorously describe the molecular and kinetic mechanisms by which cofactors in blood coagulation exert themselves. The results are aimed at elucidating the ability of cofactors to effectively mediate the hemostatic response, as well as elucidating their roles in thrombosis. The results will not only enhance our understanding of these fundamental reactions in hemostasis, but will also enable the rational design of inhibitors for treatment of thrombotic disease. There are currently several areas of interest within my laboratory. Each of these areas involves understanding the roles of cofactors in the regulation of either of the two factor X activating complexes that are central in blood clotting; the factor VIIa-tissue factor complex and the factor IXa-factor VIIIa complex.
Selected Papers and Abstracts:
- Stephenson, K., Neuenschwander, P.F., Kurdowska, A.K., Pinson, B., Price, C. (2008) Transdermal Progesterone: Effects on Menopausal Symptoms and on Thrombotic, Anticoagulant, and Inflammatory Factors in Postmenopausal Women. Int. J. Pharm. Compound. 12, 295-304.
- Villegas, K., Deadmond-Baker, K.J., Neuenschwander, P.F. (2007) Mapping of Allosteric Modulator Effects in the Active Site of Factor IXa. Blood 110(11), 791a-792a.
- Stephenson, K., Kurdoska, A., Neuenschwander, P., Loewenstein, I., Olusola, P., Pinson, B., Stephenson, D., Kinsey, R., Stephenson, J., Kapur, S., Zava, D. (2007).Transdermal Estradiol and Progesterone Improve Mood Indicators, Quality of Life and Biomarkers of Cardiovascular Disease in Perimenopausal and Postmenopausal Women. Circulation 115(8), e277.
- Neuenschwander, P.F., Williamson, S.R., Nalian, A., Baker-Deadmond, K.J. (2006) Heparin modulates the 99-loop of factor IXa: Effects on reactivity with isolated Kunitz-type inhibitor domains. J. Biol. Chem. 281, 23066-23074.
- Madiraju, M.M.V.S., Moomey, M., Neuenschwander, P.F., Muniruzzaman, S, Grimwade, J.E. & Rajagopalan, M. (2006) The Intrinsic ATPase Activity of Mycobacterium tuberculosis DnaA Promotes Rapid Oligomerization of DnaA on OriC. Molecular Microbiology 59, 1876-1890.
- Neuenschwander, P.F., Deadmond-Baker, K.J., Jones, A.D. (2006) Low Molecular Weight Heparin Modulates the Binding and Reactivity of Factor Xa towards Basic Pancreatic Trypsin Inhibitor: A Surface Plasmon Resonance and Kinetics Study. Blood 108(11), 464a.
- Neuenschwander, P.F. (2006) "Coagulation cascade: Factor X", in Encyclopedia of Respiratory Medicine, G.J. Laurent and S.D. Shapiro, eds., Elsevier Ltd., Oxford, UK, pp. 499-502.
- Neuenschwander, P.F. (2006) "Coagulation cascade: Overview", in Encyclopedia of Respiratory Medicine, G.J. Laurent and S.D. Shapiro, eds., Elsevier Ltd., Oxford, UK, pp. 478-485.
- Neuenschwander, P.F. (2006) "Coagulation cascade: Factor V", in Encyclopedia of Respiratory Medicine, G.J. Laurent and S.D. Shapiro, eds., Elsevier Ltd., Oxford, UK, pp. 490-493.
- Neuenschwander, P.F. (2006) "Coagulation cascade: Intrinsic Factors", in Encyclopedia of Respiratory Medicine, G.J. Laurent and S.D. Shapiro, eds., Elsevier Ltd., Oxford, UK, pp. 509-513.
- Neuenschwander, P.F. (2005) Evidence of Abnormal Coagulation: Production of Factor VIII alpha-Fragment in vivo. Blood. 106(11), 1020.
- Stephenson, K., Price, C., Kurdowska, A., Neuenschwander, P., Stephenson, J., Pinson, B., Stephenson, D., Alfred, D., Krupa, A., Mahoney, D., Zava, D., Bevan, M. (2004) Topical Progesterone Cream Does Not Increase Thrombotic and Inflammatory Factors in Postmenopausal Women. Blood, 104(11), 414b-415b.
- Neuenschwander PF. (2004) Exosite occupation by heparin enhances the reactivity of blood coagulation factor IXa. Biochemistry 43: 2978-2986.
- Neuenschwander PF. (2003) Regulation of Factor VIII Activity by the Factor VIIa-Tissue Factor Complex. Blood 102(11), 794a.
- Rüfer A, Neuenschwander PF, Sauer B. (2002) Analysis of Cre-loxP interaction by surface plasmon resonance: influence of spermidine on cooperativity. Anal. Biochem. 308, 90-99.
- Neuenschwander PF, Vernon, JT, Morrissey JH. (2002) Tissue factor alters the pK(a) values of catalytically important factor VIIa residues. Biochemistry. Mar 12;41(10):3364-71.
- Liaw PCY, Neuenschwander PF, Smirnov MD, Esmon CT. (2000) Mechanisms by which soluble endothelial cell protein C receptor modulates protein C and activated protein C function. J. Biol. Chem. 275:5447-5452.
- Warren DL, Morrissey JH, Neuenschwander PF. (1999) Proteolysis of blood coagulation factor VIII by the factor VIIa-tissue factor complex: generation of an inactive factor VIII cofactor. Biochemistry 38:6529-6536.
- McCallum CD, Su B, Neuenschwander PF, Morrissey JH, Johnson AE. (1997) Tissue factor positions and maintains the factor VIIa active site far above the membrane surface even in the absence of the factor VIIa Gla domain. A fluorescence resonance energy transfer study. J. Biol. Chem. 272:30160-30166.
- McCallum CD, Hapak RC, Neuenschwander PF, Morrissey JH, Johnson AE. (1996) The location of the active site of blood coagulation factor VIIa above the membrane surface and its reorientation upon association with tissue factor. A fluorescence energy transfer study. J. Biol. Chem. 271:28168-28175.
- Huang Q, Neuenschwander PF, Morrissey JH. (1996) Substrate recognition by tissue factor-factor VIIa. Evidence for interaction of residues Lys165 and Lys166 of tissue factor with the 4-carboxyglutamate-rich domain of factor X. J. Biol. Chem. 271:21752-21757.
- Payne MA, Neuenschwander PF, Johnson AJ, Morrissey JH. (1996) Effect of soluble tissue factor on the kinetic mechanism of factor VIIa: enhancement of p-guanidinobenzoate substrate hydrolysis. Biochemistry 35:7100-7106.