Bruce S. Sachais
Assistant Professor, Dept of Pathology and Laboratory Medicine
Director, Biosensor Shared Resource Facility

Cell Biology and Physiology Program

Address

207 John Morgan
3620 Hamilton Walk
Philadelphia, PA 19104

Office tel.: 215 898-0568
Lab tel.: 215 898-0569
Fax: 215 573-0252
E-mail: sachais@mail.med.upenn.edu

Link(s)

Dr. Sachais's lab webpage

EDUCATION

Lehigh University: BA (Chemistry), 1988.

Washington University: PhD (Neuroscience), 1996.

Washington University: MD (Medicine), 1996.

RESEARCH INTERESTS
Platelets, Platelet Factor 4, Atherosclerosis, Protein interactions, Murine models, Transcriptional regulation.

Key words: Platelets, Platelet Factor 4, Atherosclerosis, Protein interactions, Murine models, Tanscriptional regulation.

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DESCRIPTION OF RESEARCH

My laboratory is primarily interested in the biology and structure of platelet factor 4 (PF4). PF4 is a cationic protein found in the alpha-granules of platelets and is released upon platelet activation. It binds avidly to glycosaminoglycans on the surface of endothelial cells and is known to inhibit anti-thrombin III, resulting in increased clotting.

We are interested in the role of PF4 in several diseases, specifically atherosclerosis and heparin induced thrombocytopenia (HIT). We have found that PF4 is localized in atherosclerotic lesions and that the presence of PF4 correlated with pathological and clinical disease progression. Further, we have found that in vitro PF4 inhibits endocytosis of the LDL receptor, resulting in decreased LDL degradation and retention of LDL on the cell surface. Current studies are underway to further understand the cellular and molecular mechanisms responsible for this phenomenon and to examine the effects of PF4 on other lipoproteins and lipoprotein receptors. In vivo experiments are currently underway to further our understanding of these phenomena.

Another project in the lab is examining the molecular mechanisms of HIT. This rare but serious complication of heparin therapy is known to involve the recognition of PF4:heparin complexes by pathogenic auto-antibodies. It is also known that altering the ratio of heparin to PF4 alters the recognition of the complexes. Our working hypothesis is that the structure of the complexes formed at different heparin:PF4 ratios differs and that the structural changes are important for the expression of disease. We are investigating these structural changes and how these changes effect pathogenesis of HIT. Both in vitro and in vivo systems are being employed.

RECENT PUBLICATIONS

Pitsilos, S., Hunt, J.L., Mohler, E.R., 3rd, Prabhakar, A.M., Poncz, M., Dawicki, J., Khalapyan, T., Wolfe, M., Fairman, R., Mitchell, M., Carpnter, J., Golden, M.A., Cines, D.B., Sachais, B.S.: Platelet factor 4 localization in carotid atherosclerotic plaques: Correlation with clinical parameters. Thrombosis and Haemostasis Vol. 90: 1142-1150, 2003.

Sachais, B.S., Nassar, T., Akkawi, S., Kowalska, M.A., Bdeir, K., Leitersdorf, E., Hiss, E., Ziporen, L., Aviram, M., Cines, D., Poncz, M., Higazi, A.A-R: Platelet factor 4 enances the binding of oxidized low-density lipoprotein to vascular wall cells. J Biol Chem. Vol. 278: 6187-6193, 2003.

Sachais, B.S., Al-Roof Higazi, A., Cines, D.B., Poncz, M., Kowalska, M.A.: Interaction of platelet factor 4 with the vessel wall. Seminars in Thrombosis and Hemostasis 30(3): 351-358, June 2004.

Rouva, L., Poncz, M., McKenzie, S.E., Reilly, M.P., Arepally, G., Weisel, J.W., Nagaswami, C., Cines, D.B., and Sachais, B.S.: Ultralarge Complexes of Heparin and PF4 are Central to the Pathogenesis of Heparin-Induced Thrombocytopenia. Blood Vol. 105: 131 - 138, January 2005.

Yu G, Rux AH, Ma P, Bdeir K, Sachais BS: Endothelial expression of E-selectin is induced by the platelet specific chemokine Platelet Factor 4 through LRP in an NF-kappaB dependent manner. Blood Vol. 105: 3545-3551, May 2005.

Lab

ROTATION PROJECTS

1. PF4 activation of NF-kB and resulting pathobiology.
2. Structural mapping of monoclonal antibodies to platelet factor 4
3. Transcriptional effects of platelet specific chemokines
4. Murine models of atherosclerosis and lipoprotein metabolism

Lab personnel:

Ann Rux, PhD - Lab Manager
Tiffany Turrentine - Research Technician
Rachael Gordon – Undergraduate Student