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H. Alex Brown Wake Forest University A. Positions and Honors Positions and Employment 1992-1996 Postdoctoral Research Fellow (with Dr. Paul Sternweis ). Department of Pharmacology, University of Texas-Southwestern Medical Center at Dallas . 1996-2002 Assistant Professor of Pharmacology, Department of Molecular Medicine and Field of Biochemistry, Cornell University . 2002- Associate Professor of Pharmacology, Vanderbilt University Medical Center -Member, The Vanderbilt Institute of Chemical Biology
Other Experience and Professional Memberships: 2002-present Director, Lipidomics Laboratory, The Alliance for Cellular Signaling. 2003-present Director, Phospholipid Laboratory, LIPID MAPS 2003-present Executive Board, Biomathematics Program, Vanderbilt University . 2003-present Editorial Board, Journal of Biological Chemistry 2004 NIH-NIGMS Study Section, Special Emphasis Panel.
Current Professional Memberships: American Society for Biochemistry and Molecular Biology (ASBMB) American Society for Pharmacology and Experimental Therapeutics (ASPET) American Society for Mass Spectrometry (ASMS) Reviewer for JBC, Nature, J. Amer Society for Mass Spectrometry, JLR.
Honors and Awards: 1997- 1999 Sidney Kimmel Foundation for Cancer Research Scholar 2002-present Ingram Professor of Cancer Research (endowment).
B. Selected publications Brown, H.A., Gutowski, S., Moomaw, C.R., Slaughter, C., and Sternweis, P.C. (1993) ADP-ribosylation factor, a small GTP-dependent regulatory protein, stimulates phospholipase D activity. Cell 75 :1137-1144. Ktistakis, N., Brown, H.A., Sternweis, P.C., and Roth, M.G. (1995) Phospholipase D is present on Golgi-enriched membranes and its activation by ADP ribosylation factor is sensitive to brefeldin A. Proc. Natl. Acad. Sci. USA 92 :4952-4956. Brown, H.A., Gutowski, S., Kahn, R.A., and Sternweis, P.C. (1995) Partial purification and characterization of Arf-sensitive phospholipase D from porcine brain. J. Biol. Chem. 270 :14935-14943. Singer, W.D., Brown, H.A., Bokoch, G.M., and Sternweis, P.C. (1995) Resolved phospholipase D activity is modulated by cytosolic factors other than Arf. J. Biol. Chem. 270 :14944-14950. Brown, H.A. and Sternweis, P.C. (1995) Stimulation of phospholipase D by ADP-ribosylation factor. In Methods in Enzymology . Vol. 257. W.E. Balch, C.J. Der, and A. Hall, eds. Academic Press. Pp. 313-324. Lazarowski, E.R., Watt, W.C., Stutts, M.J., Brown, H.A., Boucher, R.C., and Harden, T.K. (1996) Enzymatic synthesis of UTP g S, a potent hydrolysis resistant agonist of P 2U -purinoceptors. Br. J. Pharmacol. 117 :203-209. Singer, W.D., Brown, H.A., Jiang, X., and Sternweis, P.C. (1996) Regulation of phospholipase D by protein kinase C is synergistic with ADP-ribosylation factor and independent of protein kinase activity. J. Biol. Chem. 271 :4504-4510. Ktistakis, N.T., Brown, H.A., Waters, M.G., Sternweis, P.C., and Roth, M.G. (1996) Evidence that phospholipase D mediates ADP ribosylation factor-dependent formation of Golgi coated vesicles. J. Cell Biol. 134 :295-306. Singer, W.D., Brown, H.A., and Sternweis, P.C. (1997) Regulation of eukaryotic phosphatidylinositol-specific phospholipase C and phospholipase D. In Annual Review of Biochemistry 66 : 475-509. Paradiso, A.M., Brown, H.A., Ye, H., Harden, T.K., and Boucher, R.C. (1999) Heterogeneous responses of cell Ca 2+ in human airway epithelium. Experimental Lung Research 25 : 277-290. Walker , S.J., Wu, W.-J., Cerione, R.A., and Brown, H.A. (2000) Activation of phospholipase D1 by Cdc42 requires the Rho insert region. J. Biol. Chem. 275 : 15665-15668. Ganley, I.G., Walker , S.J., Manifava, M., Li, D., Brown, H.A., and Ktistakis, N.T. (2001) Interaction of phospholipase D1 with a casein-kinase-2-like serine kinase. Biochem. J. 354 : 369-378. Cohen, J.S., and Brown, H.A. (2001) Phospholipases stimulate secretion in RBL mast cells. Biochemistry 40 : 6589-6597. Ivanova, P.T., Cerda, B.A., Horn, D.M., Cohen, J.S., McLafferty, F.W., and Brown, H.A. (2001) Electrospray ionization mass spectrometry analysis of changes in phospholipids in RBL-2H3 mastocytoma cells during degranulation. Proc. Natl. Acad. Sci. USA 98 : 7152-7157. Ge, M., Cohen, J.S., Brown, H.A., and Freed, J.H. (2001) ADP ribosylation factor 6 binding to phosphatidylinositol 4,5-bisphosphate-containing vesicles creates defects in the bilayer structure: An electron spin resonance study. Biophysical J. 81 : 994-1005. Brooks, M.B., Catalfamo, J.L., Brown, H.A., Ivanova, P.T., and Lovaglio, J. (2002) A hereditary bleeding disorder of dogs caused by a lack of platelet procoagulant activity. Blood 99 : 2434-2441. Walker , S.J. and Brown, H.A. (2002) Specificity of Rho insert-mediated activation of phospholipase D1. J. Biol. Chem. 277 : 26260-26267. Eisen, S. and Brown, H.A. (2002) Selective estrogen receptor modulators differentially regulate PLD catalytic activity in ER-negative breast cancer cells. Molecular Pharmacology 62:911-920. Gilman, A.G. et al., (2002) Overview of the alliance for cellular signaling. Nature 420: 703-706. Sieczkarski, S.B., Brown, H.A., and Whittaker, G.R. (2003) The role of protein kinase C b II in influenza virus entry via late endosomes. J. Virology 77:460-469. Walker , S.J. and Brown, H.A. (2003) Measurement of G protein stimulated phospholipase D activity in intact cells. In Methods in Molecular Biology vol 237: G Protein Signaling: Methods and Protocols. edited by A.V. Smrcka.Humana Press Inc., Totowa , NJ . Ge, M., Gidwani, A., Brown, H.A., Holowka, D., Baird, B., and Freed, J.H. (2003) Ordered and disordered phases coexist in plasma membrane vesicles of RBL-2H3 mast cells. An ESR Study. Biophysical J. 85: 1278-88. Gidwani, A., Brown, H.A., Holowka, D., and Baird, B. (2003) Disruption of Liquid Order by Short Chain ceramides correlates with direct inhibition of phospholipase D1 and downstream signaling by Fc e RI. J Cell Science 116:3177-87. Milne, S.B., Forrester, J.S., Ivanova, P.T., Armstrong, M.D., and Brown, H.A. (2003) Multiplexed Lipid Arrays of Anti-IgM-induced changes in the glycerophospholipid composition of WEHI-231 cells. AfCS Research Reports ( www.signaling-gateway.org/reports ). Fang, Y., Park, I.H., Wu, A.L., Huang, P., Frohman, M.A., Walker , S.J., Brown, H.A., and Chen, J. (2003) PLD1 regulates mTOR signaling and mediates Cdc42 activation of S6K1. Current Biology 13:2037-2044. Forrester, J.S., Milne, S.B., Ivanova, P.T., and Brown, H.A. (2004) Computational Lipidomics: A multiplexed analysis of dynamic changes in membrane lipid composition during signal transduction. Molecular Pharmacology 65:813-821. Ivanova, P.T., Milne, S.B., Forrester, J.S., and Brown, H.A. (2004) Lipid Arrays: New tools in the understanding of membrane dynamics and lipid signaling. Molecular Interventions 4:86-96.
C. Research Support
Ongoing Research Support: National Institutes of Health Phospholipase Activation by G-Protein-Linked Receptors This project is focused on the mechanism of activation of PLD1 by the monomeric GTPase Cdc42 and its function in the cell. The competitive renewal seeks to extend these studies by exploring the functional connections between the Cdc42-PLD pathway to cell survival via the mTOR pathway, production of extracellular survival factor (i.e., LPA), and defining the signal transduction pathways of P2Y receptors to PLD and the role of phosphatidic acid in promotion of cell proliferation and survival. Role: Principal Investigator
The Alliance for Cellular Signaling The primary goal of the Alliance for Cellular Signaling is to determine how cells process information in a context dependent manner. A variety of single and dual ligand screens are being conducted in RAW264.7 macrophages using a wide variety of techniques, including our Lipidomic Laboratory, in order to create a comprehensive cell signaling map. The emphasis of the next five years is to develop a mathematical model of "signaling nodes" that incorporate lipid second messengers into the complex integrative processes that control cellular outcomes. Role: Director of Lipidomic Laboratory. (Director of consortium, Alfred G. Gilman, UTSW).
LIPID MAPS. The goals of the LIPID MAPS project include separation and detection of the lipid species that compromise the RAW264.7 and primary mouse macrophage, development of quantitative analysis of lipid metabolites, analysis of changes in lipid composition as a function of stimulation (e.g., LPS treatment), and defining the pathways of integration between different classes of biological lipids in macrophages. The primary emphases of this project are (1) extending the technology of analytical, quantitative determination of cellular lipid composition by liquid chromatography- mass spectrometry (LC-MS) (2) determination of the lipid composition of a specified cell, and (3) to define biosynthetic pathways for each lipid and develop lipid maps that define interaction networks. Role: Director of Phospholipid Unit. (Director of consortium, Dr. Edward Dennis, UCSD).
National Cancer Institute (NCI) Lipid Profiling in Mammary Carcinomas This one year pilot grant seeks to establish conditions for developing a lipid profiling methodology in breast cancer derived cells and tumors. Role: Principal Investigator for Discovery Grant portion of SPORE in Breast Cancer Grant |
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