Current Position

Education and Training

2002-2004 Adjunct Assistant Professor, Department of Medicine, Indiana University, School of Medicine Indianapolis, Indiana

2001–2004 Assistant Investigator, Methodist Research Institute at Clarian Health, Methodist Hospital, Indianapolis, Indiana

1998-2001 Postdoctoral Fellow, Experimental Cell Research Program, Methodist Research Institute at Clarian Health, Methodist Hospital, Indianapolis, Indiana

1995–1998 Postdoctoral Fellow, Department of Biochemistry and Molecular Biology, Indiana University, School of Medicine, Indianapolis, Indiana

1995 Ph.D. (Biochemistry) University of Western Ontario, London, ON

1988 Diploma in Honors Standing (Microbiology and Immunology), University of Western Ontario,London, ON

1986 Honors B.Sc. (Biochemistry), University of Western Ontario, London, ON

Research Funding

Lab Staff

Research Investigations

1. Regulation of blood vessel formation by sphingosine 1-phosphate

The process of angiogenesis, or new blood vessel formation, is required for tissue repair following injury due to trauma or pathological conditions such as diabetes or a heart attack. Regulation of angiogenesis is a complex process involving multiple factors which may either activate or inhibit the process. Sphingosine 1-phosphate (S1P) is a bioactive phospholipid present in the blood that has recently been demonstrated to act as a potent angiogenic factor. We are studying the signalling pathways activated by S1P in endothelial and smooth muscle cells, the two primary cell types that make up blood vessels. Our current research focuses on cross-talk between the S1P specific G protein-coupled receptors and receptor tyrosine kinases. The molecular mechanisms responsible for this cross-talk and the specific pathways downstream of the tyrosine kinases are being investigated. We have recently demonstrated that the JAK-STAT pathway, a regulator of gene transcription, is activated by cross-talk between these different types of receptors. The roles played by these pathways in regulating cell migration, differentiation and cellular interactions are being examined. By understanding the mechanisms by which blood vessel formation are regulated it will be possible to enhance angiogenesis and facilitate the repair of damaged tissue, or to block the inappropriate angiogenesis associated with tumour formation.

2. Development of ERK inhibitors for cancer treatment

The extracellular signal-regulated kinase (ERK) pathway is central to a variety of cellular processes including proliferation, differentiation and survival. Following cell surface receptor activation, the classical ERK pathway (Ras – Raf – MEK – ERK) is activated. In tumour cells constitutive activation of either receptors, Ras or Raf has frequently been observed and implicated in the development of cancers. Abnormal activation of any of these upstream signalling molecules results in activation of ERK. In turn, ERK activation has been implicated in the ability of tumours to evade both normal growth control and programmed cell death (apoptosis). We have recently identified a novel small molecule inhibitor of ERK kinase activity. In breast cancer cell lines with constitutively active ERK, this inhibitor sensitizes the cells to stress induced apoptosis. We are currently studying the molecular mechanisms by which ERK inhibition sensitizes cells to apoptosis. A second area of research involves the generation of new molecules based on the structure of this inhibitor and 3-dimensional molecular modeling of the ERK structure. Currently there are no direct inhibitors of ERK activity available and the development such compounds has the potential to be of great clinical utility in the treatment of tumours.

Selected Publications

Refereed Papers

Boguslawski, G., McGlynn, P.W., Harvey, K.A., Kovala, A.T. (2004) SU1498, an inhibitor of vascular endothelial growth factor receptor 2, causes accumulation of phosphorylated ERK kinases and inhibits their activity in vivo and in vitro. Journal of Biological Chemistry 279:5716-5724

Harvey, K., Welsh, Z., Kovala, A.T., Garcia, J.G.N., and English, D. (2002) Comparative analysis of in vitro angiogenic activities of endothelial cells of heterogeneous origin. Microvascular Research 63:316-326

Boguslawski, G., Grogg, J.R., Welch, Z., Ciechanowicz, S., Sliva, D., Kovala, A.T., McGlynn, P., Brindley, D.N., Rhoades, R.A., and English, D. (2002) Migration of Vascular Smooth Muscle Cells Induced by Sphingosine 1-Phosphate and Related Lipids: Potential Role in the Angiogenic Response. Experimental Cell Research 274(2):264-274

Kovala, A.T., Harvey, K., McGlynn, P., Boguslawski, G., Garcia, J.G.N., and English, D. (2000) High efficiency transient transfection of endothelial cells for functional analysis. FASEB Journal 14:2486-2494

English, D., Welsh, Z., Kovala, A.T., Harvey, K., Volpert, O.V., Brindley, D. and Garcia, J.G.N. (2000) Sphingosine 1-phosphate released from platelets during clotting accounts for the potent endothelial cell chemotactic activity of blood serum and provides a novel link between blood hemostasis and angiogenesis. FASEB Journal 14:2255-2265

Boguslawski, G., Lyons, D., Harvey, K.A., Kovala, A.T., and English, D. (2000) Sphingosylphosphorylcholine induces endothelial cell migration and morphogenesis. Biochemical and Biophysical Research Communications 272(2):603-609

English, D., Kovala, A.T., Welch, Z., Harvey, K.A., Siddiqui, R.A., Brindley, D.N., and Garcia, J.G.N. (1999) Induction of endothelial cell chemotaxis by sphingosine 1-phosphate and stabilization of endothelial monolayer barrier function by lysophosphatidic acid, potential mediators of hematopoietic angiogenesis. Journal of Hematotherapy and Stem Cell Research 8:627-634

Harvey, K., Siddiqui, R.A., Reeves, M., Kovala, T., Dugan, M., Akard, L., and English, D. (1999) Characterization and partial purification of CD34+ progenitor cell ecto-phosphatidic acid phosphohydrolase. Biochemistry and Molecular Biology International. 47:9-23

Kovala, T., Sanwal, B.D., and Ball, E.H. (1997) Recombinant expression of a Type IV, cAMP-specific phosphodiesterase: Characterization and structure-function studies of deletion mutants. Biochemistry 36:2968-2976

Kovala, T., Lorimer, I.A.J., Brickenden, A.M., Ball, E.H., and Sanwal, B.D. (1994) Protein kinase A regulation of cAMP phosphodiesterase expression in rat skeletal myoblasts. Journal of Biological Chemistry 269:8680-8685

Ball, E.H., and Kovala, T. (1988) Mapping of caldesmon: Relationship between the high and low molecular weight forms. Biochemistry 27:6093-6098

Gordon, J., Kovala, T., and Dales, S. (1988) Molecular characterization of a prominent antigen of the Vaccina Virus envelope. Virology 167:361-369

Manuscripts in Preparation

Boguslawski, G., McGlynn, P.W., Harvey, K.A., Griffith, J., Kovala, A.T. SU1498, an inhibitor of vascular endothelial growth factor receptor 2 and ERK1/2, prevents dephosphorylation of phospho-ERK and promotes apoptosis

Kovala, A.T., Krudy, M., and English, D. Signaling pathways involved in endothelial cell chemotaxis: Comparison of sphingosine 1-phosphate, hepatocyte growth factor, and vascular endothelial growth factor induced chemotaxis

Kovala, A.T., McGlynn, P.W. and Harvey, K.A. Sphingosine 1-phosphate activates the Janus kinase – signal transducer and activator of transcription (JAK-STAT) pathway in endothelial cells by transactivation of vascular endothelial growth factor receptor-2

Abstracts

Kovala, A.T., McGlynn, P.W. and Harvey, K.A. (2004) The JAK-STAT Pathway in Endothelial Cells is Activated by Sphingosine 1-Phosphate and Vascular Endothelial Growth Factor. Keystone Symposia, Jaks and Stats: Development to Disease (E2) Whistler, British Columbia, April 15-20

Kovala, A.T., McGlynn, P., Harvey, K.A., Krudy, M., and English, D. (2002) Involvement of Rho and Rac in Sphingosine 1-Phosphate-Induced Angiogenesis. Keystone Symposia, Angiogenesis in Cancer and Other Diseases: From Genes to Function to Therapy (Z2) Banff, Alberta, Feb. 8-12,

Kovala, A.T., Krudy, M., Harvey, K., McGlynn, P., and English, D. (2001) Signaling Pathways Involved in Sphingosine 1-Phosphate-Induced Chemotaxis of Endothelial Cells. FASEB Journal 15(5):A949, Experimental Biology, Orlando, FL, March 31-April 4.

Kovala, T., Harvey, K.A., McGlynn, P., Boguslawski, G., Garcia, J.G.N., and English, D. (2000) High Efficiency Transient Transfection of Endothelial Cells Demonstrates the Involvement of the G-protein ??-subunit in Sphingosine 1-Phosphate Induced Chemotaxis. Molecular Biology of the Cell 11.951 American Society for Cell Biology, 40th Annual Meeting, San Francisco, CA, Dec 9-13.

Kovala, T., Harvey, K.A., and English, D. (2000) A High Efficiency Method for the Cotransfection and Green Fluorescent Protein Based Isolation of Transiently Transfected Endothelial Cells. Indiana University Scientific Session 2000

English, D., Welch, Z., Harvey, K., Kovala, A.T., Brindley, D.N., Garcia, J.G.N. (2000) Sphingosine 1-phosphate: A link between blood clotting and angiogenesis. Keystone Symposium, Experimental and Clinical Regulation of Angiogenesis. Salt Lake City, UT March 2-7

Siddiqui, R.A., Burtschi, D., Harvey, K., Kovala, T., and English, D. (1999) A Cellular Receptor for Phosphatidic Acid. Biochemistry and Molecular Biology, San Francisco, CA

Kovala, T., Zhang, X., Vik, T., and DePaoli-Roach, A.A. (1998) AKT control of glycogen synthase involves GSK3 but not the Glycogen-associated protein phosphatase. Indiana University Scientific Session 1998

Kovala, T., Ball, E.H., and Sanwal, B.D. (1994) Bacterial Expression and Purification of a Low Km cAMP Phosphodiesterase From Rat Skeletal Myoblasts. Canadian Federation of Biological Societies, CFBS Proceedings, 37th Annual Meeting. Montreal, Quebec

Kovala, T., Lorimer, I.A.J., Brickenden, A.M., Ball, E.H. and Sanwal, B.D. (1993) Protein Kinase A Regulation of cAMP Phosphodiesterase Expression in Rat Skeletal Myoblasts. Rossiter Research Conference, Proceedings. Barrie, Ontario

Lo, T.C.Y., Kudo, P., Kovala, T., Xia, L., and Singal, H.R. (1990) The Presence of Two Transcripts For The Hexose Transporters In Undifferentiated Rat Myoblasts. Journal of Cellular Biochemistry, Supplement 14E. pp26