University of Pennsylvania: School of Veterinary Medicine

Bruce D. Freedman V.M.D., Ph.D.

Associate Professor of Pathology

Department of Pathobiology
368E Old Vet Building
3800 Spruce Street
School of Veterinary Medicine
University of Pennsylvania
Philadelphia , PA 19104-6010

Qualifications

Ph.D., University of Pennsylvania
VMD, University of Pennsylvania
M.S., Pennsylvania State University
B.S., Dickinson College

Research Interests

The main focus of the laboratory is signaling pathways that regulate lymphocyte and macrophage development and function. Recent efforts have focused on the regulation of intracellular Ca2+ and its role in directing distinct fates of multipotent T and B cells and macrophages. Our approach is to understand how diverse and complex inputs (antigen, coactivating, and inhibitory stimuli) are encoded as functionally specific Ca2+ signals, which are translated into distinct immune responses. Current efforts are focused on defining the regulation of calcium entry channels in lymphocytes and macrophages. In B cells we have identified at least three novel calcium-permeant non-selective cation channels (NSCCs). These are distinct from calcium release activated calcium (CRAC) channels, which are believed to be the primary antigen receptor-activated calcium entry pathway in lymphocytes. NSCCs are selectively activated in response to innate stimuli including mechanical stress, and also by pathogen (bacterial and viral proteins) associated molecules (PAMPS) via production of arachidonic acid derived inflammatory mediators. The role and regulation of these NSCCs, and crosstalk between pathways involved in activation CRAC channels is the focus of ongoing efforts in the lab

A second interest of the lab is bacterial and viral-mediated signaling in lymphocytes and macrophages. One project focuses on the viral and cellular determinants of HIV-1 tropism and pathogenesis, and the consequences of viral signaling on immune function. We have defined novel signaling pathways activated in human macrophages and T cells by HIV-1 envelope protein (gp120) upon interaction with CD4 and chemokine receptors. Our continuing goal is to understand the functional consequences of this signaling on virus entry, post-entry steps of viral replication, and target cell functions.

Selected Publications : Search PubMed for articles

1. Freedman, B.D., Price, M. and Deutsch C., 1992. Evidence for voltage modulation of IL-2 production in mitogen-stimulated human peripheral blood lymphocytes. Journal of Immunology. 149:3784-3794.

2. Freedman, B.D., Fleischmann, B.K., Punt, J., Hashimoto, Y., Gaulton, G., and Kotlikoff, M.I., 1995. Identification of Kv1.1 expression by murine CD4 -CD8 - thymocytes: A role for voltage-dependent K⁺ channels in murine thymocyte development. Journal of Biological Chemistry. 270:22406-22411.

3. Freedman, B.D., Liu Q.H., Gaulton, G., Kotlikoff, M.I., Heschler, J., and Fleischmann, B.K., 1999. ATP-evoked Ca²⁺ transients and currents in murine thymocytes: Possible role for P2X receptors in death by neglect. European J.l of Immunol. 29:1635-1646.

4. Freedman, B.D., Liu, Q.H., Somersan, S., Kotlikoff, M.I., and Punt, J.A., 1999. Receptor avidity and costimulation specify the Ca²⁺_i signaling pattern in CD4⁺ CD8⁺ thymocytes. Journal of Experimental Medicine. 190:943-953.

5. Liu, Q-H, Williams, D. A., McManus, C., Baribaud, F., Doms, Schols, D., De Clercq, E.R. W., Kotlikoff, M. I., Collman R. G., and Freedman B. D., 2000. HIV-1 gp120 and chemokines activate ion channels in primary macrophages through CCR5 and CXCR4 stimulation. Proceedings of the National Academy of Sciences . 97:4832-4837.

6. Liu, Q-H, Fleischmann, B.K., Hondowicz, B., Maier, C., Turka, L., Yui, K., Kotlikoff, M.I., Wells, A.D., and Freedman, B.D., 2002. Modulation of Kv channel expression and function by TCR and costimulatory signals during peripheral CD4⁺ lymphocyte differentiation. J. Experimental Medicine. 196: 897-909.

7. Wells, A.D., Liu, Q-H, Hondowicz, B.H., Zhang, J., Turka, L.A. , and Freedman, B.D., 2003. Regulation of T cell activation and tolerance by PLCg 1-dependent integrin avidity modulation. Journal of Immunology. 170:4127-4133.

8. Liu, Q-H., Liu, X., Wen, Z., Hondowicz, B., King, L.B., Monroe , J., and Freedman, B.D., 2005. Distinct calcium channels regulate responses of primary B lymphocytes to BCR engagement and mechanical stimuli . Journal of Immunology. 174:68-792.

9. Zhu, P., Liu, X., Labelle, E., Freedman, B.D.,2005. Mechanisms of hypotonicity-induced calcium signaling and integrin activation by arachidonic acid-derived inflammatory mediators in B cells. Journal of Immunology. 175:4981-4989.

10. Liu, X., Zhu, P., Freedman, B.D., Multiple eicosanoid-activated non-selective cation channels regulate B cell adhesion to integrin ligands. (in press, American Journal of Physiology, Cell Physiology).