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Hironao Wakabayashi, M.D., Ph.D.

Contact Information

Phone Numbers

Office: (585) 273-4906

Research Labs

Biography

Hemophilia A is a bleeding disease caused by deficiency or defect of a protein called blood coagulation factor VIII. Since 1992 recombinant factor VIII product was introduced, the periodical (very frequent) supplement of this protein by injection through vein has been a major therapeutic approach. Our research focuses on the development of new factor VIII product which has better activity. Consequently the frequency of injection as well as a risk of heavy bleeding incident would be reduced. Hemophilia A patients are usually a boy. Less injection would be very helpful to ease them.
I started my career as a pathologist and obtained a training of cell biology and protein chemistry. I have been working on current study for 8 years.

Professional Background

Hironao Wakabayashi earned M.D. after 6 year education at Fukushima Medical School in Japan on 1988. In the Department of Pathology (II) at Fukushima Medical School he enrolled Ph.D. program. He studied on cancer invasion and metastasis and earned Ph.D. at 1992. He obtained postdoctoral training at University of Texas MD Anderson Cancer Center in Huston working on the same subject until he had an appointment as a Research Assistant Professor at The Institute for Molecular Medicine at Irvine, CA on 1996. Since 1999 he has been working as a Research Assistant Professor in the Department of Biochemistry and Biophysics at University of Rochester studying on the structural and functional analyses of blood coagulation factor VIII.

Research

Structural and functional analyses of factor VIII

Factor VIII functions as a cofactor for the serine protease factor IXa in the surface-dependent conversion of zymogen factor X to the serine protease, factor Xa. Deficiency of factor VIII activity results in a marked reduction of factor IXa activity and in the subsequent rates of factor Xa generated during the propagation phase of coagulation.
My research focuses on the role of metal ions for structural integrity and function of factor VIII. Active factor VIII can be reconstituted by combining the isolated subunits in the presence of Ca2+ or Mn2+. Ca2+ had little effect on inter-subunit affinity yet converted the inactive dimer to an active form. Alternatively, Cu2+ enhanced the inter-subunit affinity ~100-fold but yielded a dimer lacking cofactor activity. Site-directed mutagenesis is employed to identify residues important in Ca2+ binding to factor VIII and resultant effects of this binding on activity. Several acidic amino acids within segment 110-126 of the A1 domain of factor VIII that likely participate in the coordination of Ca2+ necessary for generation of maximal cofactor specific activity.

Recent Publications

Wakabayashi, H., Zhou, Q., Varfaj, F., and Fay, P. J.
A3 Domain Residue Glu1829 Contributes to A2 Subunit Retention in Factor VIIIa J. Thromb. Haemost., in press.

Varfaj, F., Neuberg, J., Jenkins, P. V., Wakabayashi, H., and Fay, P. J.
Role of P1 Arg in Activated Protein C - Catalyzed Inactivation of Factor VIIIa. Biochemical J. 396, 355-362, 2006.

Wakabayashi, H., Zhou, Q., Nogami#, K., Ansong, C., Varfaj, F., Miles, S., and Fay, P. J.
pH-dependent association of factor VIII chains: Enhancement of affinity at physiological pH by Cu2+. Biochim. Biophys. Acta 1764,1094-1101, 2006.

Nogami, K., Zhou, Q., Myles, T., Leung, L. L. , Wakabayashi, H., and Fay, P. J.
Exosite-interactive Regions in the A1 and A2 Domains of Factor VIII Facilitate Thrombin-catalyzed Cleavage of Heavy Chain.
J. Biol. Chem. 280, 18476-18487, 2005.

Nogami, K., Zhou, Q., Wakabayashi, H., and Fay, P. J. Thrombin-catalyzed activation of factor VIII with His substituted for Arg372 at the P1 site.
Blood 105, 4362-4368, 2005.

Wakabayashi, H., Su, Y. C. , Ahmad, S. S. , Walsh, P. N. , and Fay, P. J.
A Glu113Ala Mutation within a Factor VIII Ca(2+)-Binding Site Enhances Cofactor Interactions in Factor Xase.
Biochemistry 44, 10298-10304, 2005.

Nogami, K., Wakabayashi, H., Ansong, C., and Fay, P. J. Localization of a pH-dependent, A2 subunit-interactive surface within the factor VIIIa A1 subunit.
Biochim. Biophys. Acta 1701, 25-35, 2004.

Nogami, K., Freas, J., Manithody, C., Wakabayashi, H., Rezaie, A. R. , and Fay, P. J.
Mechanisms of interactions of factor X and factor Xa with the acidic region in the factor VIII A1 domain.
J. Biol. Chem. 279, 33104-33113, 2004.

Nogami K., Lapan K.A., Zhou Q., Wakabayashi H., and Fay P.J.
Identification of a Factor Xa-interactive Site within Residues 337-372 of the Factor VIII Heavy Chain.
J. Biol. Chem. 279, 15763-15771, 2004.

Wakabayashi H., Freas J., Zhou Q., and Fay P.J.
Residues 110-126 in the A1 domain of factor VIII contain a Ca2+ binding site required for cofactor activity.
J. Biol. Chem. 279, 12677-12684, 2004.

Wakabayashi H., Zhen Z., Schmidt K.M., and Fay P.J.
Mn2+ binding to factor VIII Subunits and its effect on cofactor activity.
Biochemistry 42, 145-153, 2003.

Wakabayashi H., Schmidt K.M., and Fay P.J.
Ca2+ binding to both the heavy and light chains of factor VIII is required for cofactor activity.
Biochemistry 41, 8485-8492, 2002.

Wakabayashi H., Koszelak M., Mastri, M., and Fay P.J Metal-ion independent factor VIII subunit association and the role of calcium and copper for its affinity and activity.
Biochemistry 40, 10293-10300, 2001.

Credentials

Faculty Appointments

Education

1988
MD | Japan-Fukushima Med Coll
Medicine

1992
PhD | Japan-Fukushima Med Coll
Pathology

Publications

Journal Articles

5/2017
Yang F, Zhang L, Wakabayashi H, Myers J, Jiang Y, Cao Y, Jimenez-Ortigosa C, Perlin DS, Rustchenko E. "Tolerance to Caspofungin in Candida albicans Is Associated with at Least Three Distinctive Mechanisms That Govern Expression of FKS Genes and Cell Wall Remodeling." Antimicrobial agents and chemotherapy.. 2017 May 0; 61(5)Epub 2017 Apr 24.

12/2016
Suwunnakorn S, Wakabayashi H, Rustchenko E. "Chromosome 5 of Human Pathogen Candida albicans Carries Multiple Genes for Negative Control of Caspofungin and Anidulafungin Susceptibility." Antimicrobial agents and chemotherapy.. 2016 Dec 0; 60(12):7457-7467. Epub 2016 Nov 21.

5/2016
Monaghan M, Wakabayashi H, Griffiths AE, Fay PJ. "Stabilizing interactions between D666-S1787 and T657-Y1792 at the A2-A3 interface support factor VIIIa stability in the blood clotting pathway." Journal of thrombosis and haemostasis : JTH.. 2016 May 0; 14(5):1021-30. Epub 2016 Mar 21.

Books & Chapters

1998
Chapter Title: Transfilter cell invasion assays
Book Title: Cell Biology: A laboratory Handbook
Author List: Wakabayashi, H. and Nicolson G. L.
Edited By: Celis J.E.
Published By: Academic press1998 in San Diego

1993
Chapter Title: Determination of invasive ability into Matrigel or Collagen.
Book Title: Cell Culture Handbook
Author List: Wakabayashi, H.
Edited By: Suzuki T.
Published By: Chugain Igaku Co.1993 in Tokyo, Japan

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