1985 - Rochester Institute of Technology, B.S. Chemistry (ACS)
1990 - State University of New York at Stony Brook, Ph.D. Biochemistry & Molecular Biology
- Blood coagulation
- Macromolecular interactions
- Protein structure/function
- Dysfunctional and pathological coagulation reactions
- Structure/function studies of factor IXa and its cofactors
- Hemocompatible surfaces
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 majority of my research has emphasized understanding various biomolecular interactions and the elucidation of structure/function correlates with respect to blood coagulation proteases and their cofactors. The broad 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 and their contributions to other pathophysiologic states. 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. Two of these areas involve understanding the molecular details of cofactor function in the regulation of either of the two factor X activating complexes; the factor VIIa-tissue factor complex and the factor IXa-factor VIIIa complex. In addition to these main thrusts, over the past few years I have developed a strong interest in understanding the dysfunctional coagulation that occurs in various pulmonary diseases and its relation to the observed lung pathologies and clinical outcomes. The ultimate goal is to identify novel therapeutic targets and/or therapeutic strategies that can be used in the clinic to diagnose and/or treat dysfunctional coagulation in acute lung injury and other scenarios. More recently, I have developed a related interest in influenza and its effect on the coagulant system during infection. Aside from enabling better treatments and prevention of lung diseases, it is hoped that elucidation of the complex intersystem dynamics of the coagulation, inflammatory and immune systems (as readily observed in acute lung injury) would give us insight into potential control/treatment/diagnostic options for more broadly-related coagulation dysfunction.
Subramaniam, R., Barnes, P., Fletcher, K., Hillberry, Z, Boggaram, V, Neuenschwander, P.F., Shams, A. (2014) Protecting against post-influenza bacterial pneumonia by increasing phagocyte recruitment and ROS production. J. Infectious Diseases 209(11):1827-36. doi: 10.1093/infdis/jit830. Epub 2013 Dec 23. PMID 24367039
Bhandary, Y.P., Shetty, S.K., Marudamuthu, A.S., Ji, H-L., Neuenschwander, P.F., Boggaram, V., Fu, J., Morris, G.F., Idell, S., Shetty, S. (2013) Regulation of alveolar epithelial injury and lung remodeling by p53-mediated changes in urokinase and plasminogen activator inhibitor-1. Am J Pathol. 183(1):131-43. doi:10.1016/ j.ajpath.2013.03.022. Epub 2013 May 8. PMID 23665346
Stephenson, K., Neuenschwander, P.F., Kurdowska, A.K. (2013) The effects of compounded bioidentical transdermal hormone therapy on hemostatic, inflammatory, immune factors; cardiovascular biomarkers; quality-of-life measures; and health outcomes in perimenopausal and postmenopausal women. Int J Pharm Compd. 17(1):74-85. PMID 23627249
Wang, X., Barnes, P.F., Huang, F., Alvarez, I.B., Neuenschwander, P.F., Sherman, D.R. Samten, B. (2012) Early Secreted Antigenic Target of 6-kD Protein of Mycobacterium tuberculosis Primes Dendritic Cells to Stimulate Th17 and Inhibit Th1 Immune Responses J Immunol. 189(6):3092-103. doi:10.4049/jimmunol.1200573. Epub 2012 Aug 17. PMID 22904313
Neuenschwander, P.F., Deadmond, K., Zepeda, K., Rutland, J. (2012) Correlation of Factor IXa Subsite Modulations with Effects on Substrate Discrimination. J Thromb Haemost 10, 382-389. doi: 10.1111/j.1538-7836.2011.04605.x. PMID 22212890
Pang, X., Cao, G. Neuenschwander, P.F., Haydel, S.E., Hou, G. and Howard, S.T. (2011) The ß-propeller gene Rv1057 of Mycobacterium tuberculosis has a complex promoter directly regulated by both the MprAB and TrcRS two-component systems. Tuberculosis 91(S1), S142-S149. doi: 10.1016/j.tube.2011.10.024. Epub 2011 Nov 17. PMID 22099420
Sen, P., Neuenschwander, P.F., Pendurthi, U.R., Rao, L.V.M. (2010) Analysis of factor VIIa binding to relipidated tissue factor by surface plasmon resonance. Blood Coag. & Fibrinol. 21(4), 376-9. doi: 10.1097/MBC.0b013e328333b084. PMID 20305542
Shetty. R.S., Bhandary, Y.P., Velusamy, T., Shetty, P., Bdeir, K., Gyetko, M.R., Cines, D.C., Idell, S., Neuenschwander, P.F., Ruppert, C., Gunther, A., Shetty, S. (2010) Induction of Tissue Factor by Urokinase in Lung Epithelial Cells. Am. J. Resp. Crit. Care Med. 181(12), 1355-66. doi: 10.1164/rccm.200901-0015OC. Epub 2010 Mar 1. PMID 20194819
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.
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. Epub 2006 Jun 9. PMID 16766524
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. PMID 16553890
Neuenschwander, P.F. (2004) Exosite Occupation by Heparin Enhances the Reactivity of Blood Coagulation Factor IXa. Biochemistry 43: 2978-2986. PMID 15005634
Rüfer, A., Neuenschwander, P.F., & Sauer, B. (2002) Analysis of Cre/loxP Interaction by Surface Plasmon Resonance: Influence of Spermidine on Cooperativity. Anal. Biochem. 308, 90-99. PMID 12234468
Neuenschwander, P.F., Vernon, J.T., & Morrissey, J.H. (2002) Tissue Factor Alters the pKa Values of Catalytically Important Factor VIIa Residues. Biochemistry 41, 3364-3371. PMID 11876644
Liaw, P.C.Y., Neuenschwander, P.F., Smirnov, M.D., & Esmon, C.T. (2000) Mechanisms By Which Soluble Endothelial Cell Protein C Receptor Modulates Protein C and Activated Protein C Function. J. Biol. Chem. 275, 5447-5452. PMID 10681521
Warren, D.L., Morrissey, J.H., & Neuenschwander, P.F. (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. PMID 10350471