Dr Tamas Zakar
My area of research is the physiology and pathophysiology of parturition. With the help of my coworkers, I am studying the role of prostaglandins in the process of human birth. Prostaglandins are locally acting hormones that perform multiple functions including the control of labour. In the pregnant uterus, increased amounts of prostaglandins are produced at term, which initiates labour by inducing cervical softening and myometrial contractions. The mechanisms that increase intrauterine prostaglandin concentrations and determine the time of labour onset are unknown. Our overall goal is to address this problem and determine how prostaglandin levels are regulated in the uterus at parturition. We hypothesise that the activity of the genes that encode the key enzymes of prostaglandin biosynthesis and degradation changes coordinately in the gestational tissues at term, which results in increased prostaglandin levels and uterine activation. Dysregulation of these genes may lead either to preterm labour and premature birth, or to postterm pregnancy and protracted labour. Within the pathway of prostaglandin biosynthesis, we focus on the two genes that encode the two isoenzymes of prostaglandin H-synthase (COX-1 and COX-2). Within the pathway of prostaglandin degradation, we focus on 15-hydroxyprostaglandin dehydrogenase (PGDH). The COX enzymes control the rate of prostaglandin production, and PGDH controls the rate of prostaglandin inactivation. We examine the regulation of these genes and their products in tissues obtained from pregnant women, in cell cultures derived from the gestational tissues, and in animals that provide a model for the human parturition process. We study the involvement of the steroid hormones of pregnancy and the role of the stress-activated signalling systems in the regulation of COX-1, 2, and PGDH expression. The methods include biochemical and molecular biology techniques such as quantitative RT-PCR, nuclear run-on, chromatin immunoprecipitation, in vivo footprinting, immunoblot, ELISA, and RIA. A group of talented researchers and graduate students forms the core of the team that pursues these projects vigorously and with dedication.
Non-refereed Journal Articles
Hirst, J. J., Teixeira, F. J., Zakar, T., Olson, D. M. Prostaglandin endoperoxide H synthase-1 and -2 mRNA levels in human amnion with spontaneous labor onset. J. Clin. Endocrinol. Metab. 80: 517-523, 1995.
Zakar, T., Hirst, J. J., Mijovic, J. E., Olson, D. M. Glucocorticoids stimulate the expression of prostaglandin endoperoxide H synthase-2 in amnion cells. Endocrinology, 136:1610-1619, 1995.
Hirst, J. J., Teixeira, F. J., Zakar, T., Olson, D. M. Prostaglandin H synthase expression increases in human gestational tissues with spontaneous labor onset. Reproduction, Fertility and Development, 7:633-637, 1995
Zakar, T., Mitchell, B. F. The endocrinology of late pregnancy and parturition. In: Advances in Organ Biology, Volume 1, Eds: E. E. Bittar and T. Zakar. Jai Press, Inc. Greenwich, Connecticut, 1996, pp.:153-173.
Radomski, M. W., Zakar, T., Salas, E. Methods of working with nitric oxide in platelets. In: Methods in Enzymology. Ed.: L. Packer, Academic Press, 1996.
Zakar, T., Olson, D. M., Teixeira, F. J., Hirst, J. J. Regulation of prostaglandin endoperoxide H2 synthase in term human gestational tissues. Acta Physiologica Hungarica, 84:109-118, 1996.
Mijovic, J. E., Zakar, T., Nairn, T., Olson, D. M. Prostaglandin endoperoxide H synthase -2 expression and activity increases with term labor in human chorion. American Journal of Physiology,272 (Endocrinol. Metab. 35): E832-E840, 1997.
Zakar, T., Mijovic, J. E., Eyster, K. M., Bhardvaj, D., Olson, D. M. Regulation of prostaglandin H2 synthase expression in primary human amnion cells by tyrosine kinase dependent mechanisms. Biochimica et Biophysica Acta 1391:37-51, 1998.
Hirst, J. J., Mijovic, J. E., Zakar, T., Olson, D. M. Prostaglandin endoperoxide H synthase-1 and -2 mRNA levels and enzyme activity in human decidua at term labor. Journal of the Society for Gynecologic Investigation, 5:13-20, 1998.
Zakar, T., Mijovic, J. E., Olson, D. M. Prostaglandin endoperoxide H synthase-2 expression in human amnion cells: Involvement of tyrosine kinases in the regulation. In: Recent Advances in Prostaglandin, Thromboxane, and Leukotriene Research (Eds.: H. Sinzinger, J. E. Vane, B. Samuelsson, R. Paoletti, P. W. Ramwell, P.Y.-K. Wong), Plenum Press, New York, 1998, pp.415-418.
Mijovic, J. E., Zakar, T., Nairn, T. K., Olson, D. M. Prostaglandin endoperoxide H synthase (PGHS) activity and PGHS-1 and PGHS-2 mRNA abundance in human chorion throughout gestation and with preterm labor. J. Clin. Endocrinol. Metab., 83:1358-1367, 1998.
Mijovic, J. E., Zakar, T., Olson, D. M. Prostaglandin endoperoxide H synthase (PGHS) -1 and -2 expression and activity in human chorion and decidua. Trophoblast Research 11:209-228, 1998.
Zakar, T., Mitchell, B. F. The endocrinology of late pregnancy and parturition. In: Principles of Medical Biology, Volume 12: Reproductive Endocrinology and Biology, (Eds: E. E. Bittar, N. Bittar) Jai Press, Inc. Greenwich, Connecticut, 1998, pp.167-182.
Olson, D. M., Mijovic, J. E., Zakar, T., Cook, J. Current concepts in prostaglandin regulation for birth. Journal of the Society of Obstetricians and Gynaecologists of Canada 21: 230-237, 1999
Mijovic, J. E., Zakar, T., Angelova, J., Olson, D. M. Prostaglandin endoperoxide H synthase mRNA expression in the human amnion and decidua during pregnancy and in the amnion at preterm labor. Molecular Human Reproduction 5:182-187, 1999
Zakar, T., Mijovic, J. E., Olson, D. M. Tyrosine kinase inhibitors block the glucocorticoid stimulation of prostaglandin endoperoxide H synthase expression in amnion cells. Canadian Journal of Physiology and Pharmacology, 77:138-142, 1999
Mijovic, J. E., Demianczuk, N., Olson, D. M., Zakar, T. Prostaglandin endoperoxide H synthase expression in the fetal membranes correlates with fetal fibronectin concentration in the cervico-vaginal fluids at term: Evidence of enzyme induction before the onset of labor. British Journal of Obstetrics and Gynaecology, 107:267-273, 2000
Zakar, T., Hertelendy, F. Regulation of prostaglandin synthesis in the human uterus, The Journal of Maternal-Fetal Medicine, 10:223-235, 2001.
Johnson, R. F., Mitchell, C. M., Giles, W. B., Walters, W. A., Zakar, T. The in vivo control of prostaglandin synthase -2 (PGHS-2) mRNA expression in the human amnion at parturition. Journal of Clinical Endocrinology and Metabolism, 87:2816-2823, 2002 (Special Issue: "The Impact of the Human Genome on Endocrinology).
Membership of Societies and Professional Bodies
- Endocrine Society of Australia
- Perinatal Society of Australia and New Zealand
- Society for Gynecologic Investigation
- Society for the Study of Reproduction