Despite enormous efforts, preterm birth (<37 weeks of gestation) remains the leading cause of morbidity and mortality in babies. Our laboratory studies the various genetic, physiological and environmental factors that contribute to both term and preterm labour.
Our long-term objective is to translate basic science discoveries to practical prognostic and therapeutic applications to improve the health of mothers and babies.
The prostaglandin F receptor (PTGFR) and birth
We are defining the regulation and role of the prostaglandin (PG)F2a receptor (FP) in the control of parturition at term and preterm.
Single nucleotide polymorphisms and stress in the etiology of spontaneous preterm birth
Currently, the majority of preterm deliveries are still unexplained. Pregnancy and parturition involve complex pathways in both mother and fetus, some of which may be termed environmental. These include stress, inflammation, hemorrhage and pathologic uterine distension. Most commonly. they are present in various degrees of combination. In addition to these environmental factors, there is also a strong genetic basis for preterm birth.
In new studies, we are exploring gene-environment interactions and seeking a transcriptomic predictor of preterm birth.
With an international group of scientists led by PreHOT member, Craig Pennell (University of Western Australia), and sponsored by PreHOT, the World Health Organization and the March of Dimes, we just recently announced a SNP signature that is highly associated with Caucasian women who delivered preterm at < 34 weeks of gestation. We have confirmed that this signature is robust, i.e. it is replicated (p<1x10^-8) in similar cohorts of women around the world, including our Edmonton cohort.
We have filed a provisional patent for the signature. The prognostic test we will develop to predict risk for women of preterm delivery can be taken by non-pregnant women.
Studies on mechanisms of uterine activation for labour: interactions between corticotropin-releasing hormone and prostaglandins
During most of pregnancy, the myometrium remains in a relatively quiescent state until it is activated to initiate the contractions required for labour and delivery of the baby.
Although the mechanisms that control the transition of the myometrium from a quiescent to an active state remain unknown, increasing lines of evidence suggest the local stimulators, corticotropin-releasing hormone (CRH) and prostaglandins (PGs), may have a synergistic relationship of mutual amplification that leads to uterine activation and labour.
Our objective is to investigate the interactions between CRH and PGs in human pregnant myometrium and thereby explore the mechanisms of uterine activation for labour. We intend to identify targets for intervention to delay preterm birth.
Recently we found that PGF and its receptor, PTGFR, are points of convergence of several pathways and also amplifiers of uterine activation (i.e. they stimulate the expression of uterine activation factors).
Studies on drugs that delay preterm labour
Most drugs used by clinicians to delay preterm labour and prolong pregnancy are quite ineffective or have several maternal and fetal side effects. In part this is due to the fact that nearly all were designed originally for some other health problem.
Contemporary strategies for designing better, more specific and safer drugs to delay preterm labour include targeting events that occur earlier in the cascade of physiological and biochemical events leading to labour and to target mechanisms that are specific to uterine tissues.
In our collaborative efforts with Drs. Sylvain Chemtob from the University of Montreal and Gerlinde Metz from the University of Lethbridge, we are finding that targeting cytokine receptors is effective in delaying preterm and term labour in rodent models, and targeting the receptor for PGF, PTGFR, in the uterus is producing very promising results and possibly new drugs that are commercializable.
Gomez-Lopez N , Vadillo-Perez L, Hernandez-Carbajal A, Olson DM , Vadillo-Ortega F. Specific inflammatory microenvironments in the zones of the fetal membranes at term delivery. Accepted for publication. 2011. American Journal of Obstetrics and Gynecology.
Xu C, You X, Gao L, Zhang L, Hu R, Hui N, Olson DM , Ni X. Expression of ATP-sensitive channels in human pregnant myometrium. Reproductive Biology and Endocrinology. 2011 Mar 21;9(1):35. [Epub ahead of print]
Gracie SK, Andrew W. Lyon AW, Kehler HL, Pennell CE, Dolan SM, McNeil DA, Siever JE, McDonald SW, Bocking AD, Lye SJ, Hegadoren KM, Olson DM , Tough SC. All Our Babies Cohort Study: Recruitment of a cohort to predict women at risk of preterm birth through the examination of gene expression profiles and the environment, 2011. BMC Pregnancy and Childbirth, 10:87.
Gomez-Lopez N , Vadillo-Perez L, Nessim S , Olson DM , Vadillo-Ortega F. Choriodecidua and amnion exhibit selective chemotaxis during term labor. 2011. American Journal of Obstetrics and Gynecology, Apr;204(4):364.e9-364.e16.
Tanaka S , Stock SJ, Yamamoto Y , Kondejewski J, Olson DM. Understanding Perinatal Mortality, 2010. Obstetrics, Gynaecology, and Reproductive Medicine, 20:317-322.
Estrada-Gutierrez G, Gomez-Lopez N , Zaga-Clavellina V, Giono-Cerezo S, Espejel-Nuñez M, Gonzalez-Jimenez A, Espino y Sosa S, Olson DM , Vadillo-Ortega F. Interaction between pathogenic bacteria and intrauterine leukocytes triggers alternative molecular signaling cascades leading to labor in women, 2010. Infection and Immunity 78:4792-4799.
Hay A, Wood S, Olson DM, Slater D. Labour is associated with decreased expression of the prostaglandin F 2 a ? receptor (PTGFR) and a novel PTGFR splice variant in human myometrium but not decidua, 2010. Molecular Human Reproduction 16:752-60.
Robertson SA, Christiaens I , Zaragoza DB, Dorian C, Care A, Banks AM , Olson DM. Interleukin-6 is an essential determinant of on-time parturition in the mouse. Endocrinology, 2010 151:3996-4006.
Gomez-Lopez N , Guilbert L, Olson DM . Invasion of the leukocytes into the maternal-fetal interface during pregnancy, 2010. Journal of Leukocyte Biology 88:625-33.
Duthie K , Riddell M, Weller C, Coltan LI, Benzies K, Olson DM. Alberta's new health research paradigms: Are graduate students being prepared for interdisciplinary team research? Clinical and Investigative Medicine, 33:E213-218, 2010 Selected for commentary by the É/Exchange Working Paper Series.
Laresgoiti-Servitje E, Gomez-Lopez N, Olson DM . An immunological insight into the origins of preeclampsia, 2010. Human Reproduction Update. 16:510-24.
Gomez-Lopez N, Laresgoiti-Servitje E, Olson DM , Estrada-Gutierrez G, Vadillo-Ortega F. The role of chemokines in term and premature rupture of the membranes: a review, 2010. Biology of Reproduction Biol Reprod . 82:809-14.
Yamamoto Y , Olson DM , van Bennekom M, Brindley DN, Hemmings DG, Increased expression of enzymes for sphingosine 1-phosphate turnover in human decidua during late gestation, 2010. Biol Reprod 82(3):628-35.
Beyea J , Olson DM , Harvey S. Growth hormone-dependent changes in the rat lung proteome during alveolarization. Molecular and Cellular Biochemistry,2009, 321:197-204.
Olson DM, Christiaens I , Gracie S , Yamamoto Y, Mitchell BF. Emerging tocolytics: Challenges in designing and testing drugs to delay preterm delivery and prolong pregnancy. Expert Opinion on Emerging Drugs, Invited review, 4:695-707, 2008.
Christiaens I , Zaragoza DB, Guilbert LJ, Robertson SA, Mitchell BF, Olson DM. Inflammatory processes in preterm and term parturition. Journal of Reproductive Immunology, 2008. Invited review, 79:50-57.
Brennan KA , Kaufman S, Reynolds SW , McCook BT , Kan G , Christiaens I , Symonds DM, Olson DM. Differential effects of maternal nutrient restriction through pregnancy on kidney development and later blood pressure control in the resulting offspring, 2008. American Journal of Regulatory Integrative Comparative Physiology, 295:R197-R205.
Olson, DM and Ammann, C. Role of the prostaglandins in labour and prostaglandin receptor inhibitors in the prevention of preterm labour. Front Biosci, 2007. 12: p. 1329-43.
Makino S , Zaragoza DB, Mitchell BF, Robertson S, Olson DM, Prostaglandin F 2 a and its receptor as activators of human decidua. Seminars in Reproductive Medicine, 2007. Invited review, 25:60-68,
Makino S, Zaragoza DB, Mitchell BF, Yonemoto H, Olson DM, Decidual Activation: Abundance and Localization of Prostaglandin F(2alpha) Receptor (FP) mRNA and Protein and Uterine Activation Proteins in Human Decidua at Preterm Birth and Term Birth. Placenta, 2007. 28(5-6): p. 557-565.
Zaragoza, DB, Wilson RR, Mitchell BF, Olson DM, The Interleukin 1beta-Induced Expression of Human Prostaglandin F2alpha Receptor Messenger RNA in Human Myometrial-Derived ULTR Cells Requires the Transcription Factor, NFkappaB. Biol Reprod, 2006. 75(5): p. 697-704.
Yonemoto, H, Young CB, Ross JT, Guilbert LL, Fairclough RJ, Olson DM. Changes in matrix metalloproteinase (MMP)-2 and MMP-9 in the fetal amnion and chorion during gestation and at term and preterm labor. Placenta, 2006. 27(6-7): p. 669-77.
Kossintseva, I., S. Wong, E. Johnstone, L. Guilbert, D.M. Olson, and B.F. Mitchell, Proinflammatory cytokines inhibit human placental 11beta-hydroxysteroid dehydrogenase type 2 activity through Ca2+ and cAMP pathways. Am J Physiol Endocrinol Metab, 2006. 290(2): p. E282-8.
Brennan, K.A., D.M. Olson, and M.E. Symonds, Maternal nutrient restriction alters renal development and blood pressure regulation of the offspring. Proc Nutr Soc, 2006. 65(1): p. 116-24.
Beyea, J.A., G. Sawicki, D.M. Olson, E. List, J.J. Kopchick, and S. Harvey, Growth hormone (GH) receptor knockout mice reveal actions of GH in lung development. Proteomics, 2006. 6(1): p. 341-8.
Olson, D.M., The promise of prostaglandins: have they fulfilled their potential as therapeutic targets for the delay of preterm birth? J Soc Gynecol Investig, 2005. 12(7): p. 466-78.
Hirst, J.J., H.C. Parkington, I.R. Young, H.K. Palliser, K.G. Peri, and D.M. Olson. Delay of preterm birth in sheep by THG113.31, a prostaglandin F2alpha receptor antagonist. Am J Obstet Gynecol, 2005. 193(1): p. 256-66.
Brennan, K.A., G.S. Gopalakrishnan, L. Kurlak, S.M. Rhind, C.E. Kyle, A.N. Brooks, M.T. Rae, D.M. Olson, T. Stephenson, and M.E. Symonds, Impact of maternal undernutrition and fetal number on glucocorticoid, growth hormone and insulin-like growth factor receptor mRNA abundance in the ovine fetal kidney. Reproduction, 2005. 129(2): p. 151-9.
Beyea, J.A., D.M. Olson, R.A. Vandergriend, and S. Harvey, Expression of growth hormone and its receptor in the lungs of embryonic chicks. Cell Tissue Res, 2005. 322(3): p. 379-92.
Beyea, J.A., D.M. Olson, and S. Harvey, Growth hormone expression in the perinatal and postnatal rat lung. Dev Dyn, 2005. 232(4): p. 1037-46.
Beyea, J.A., D.M. Olson, and S. Harvey, Growth hormone (GH) action in the developing lung: changes in lung proteins after adenoviral GH overexpression. Dev Dyn, 2005. 234(2): p. 404-12.
Zaragoza, D.B., R. Wilson, K. Eyster, and D.M. Olson, Cloning and characterization of the promoter region of the human prostaglandin F2alpha receptor gene. Biochim Biophys Acta, 2004. 1676(2): p. 193-202.
Williams, S.J., D.M. Olson, D.B. Zaragoza, C.L. Coulter, T.G. Butler, J.T. Ross, and I.C. McMillen, Cortisol infusion decreases renin, but not PGHS-2, EP2, or EP4 mRNA expression in the kidney of the fetal sheep at days 109-116. Pediatr Res, 2004. 55(4): p. 637-44.
Mitchell, B.F. and D.M. Olson, Prostaglandin endoperoxide H synthase inhibitors and other tocolytics in preterm labour. Prostaglandins Leukot Essent Fatty Acids, 2004. 70(2): p. 167-87.
Hosford, G.E., X. Fang, and D.M. Olson, Hyperoxia decreases matrix metalloproteinase-9 and increases tissue inhibitor of matrix metalloproteinase-1 protein in the newborn rat lung: association with arrested alveolarization. Pediatr Res, 2004. 56(1): p. 26-34.
Olson, D.M., D.B. Zaragoza, M.C. Shallow, J.L. Cook, B.F. Mitchell, P. Grigsby, and J. Hirst, Myometrial activation and preterm labour: evidence supporting a role for the prostaglandin F receptor--a review. Placenta, 2003. 24 Suppl A: p. S47-54.
Olson, D.M., The role of prostaglandins in the initiation of parturition. Best Pract Res Clin Obstet Gynaecol, 2003. 17(5): p. 717-30.
Hosford, G.E. and D.M. Olson, Effects of hyperoxia on VEGF, its receptors, and HIF-2alpha in the newborn rat lung. Am J Physiol Lung Cell Mol Physiol, 2003. 285(1): p. L161-8.
Cook, J.L., M.C. Shallow, D.B. Zaragoza, K.I. Anderson, and D.M. Olson. Mouse placental prostaglandins are associated with uterine activation and the timing of birth. Biol Reprod, 2003. 68(2): p. 579-87.
Williams, S.J., I.C. McMillen, D.B. Zaragoza, and D.M. Olson, Placental restriction increases the expression of prostaglandin endoperoxide G/H synthase-2 and EP2 mRNA in the fetal sheep kidney during late gestation. Pediatr Res, 2002. 52(6): p. 879-85.
Mijovic, J.E., T. Zakar, D.B. Zaragoza, and D.M. Olson, Tyrphostins inhibit lipopolysaccharide induced preterm labor in mice. J Perinat Med, 2002. 30(4): p. 297-300.
Hosford, G.E., K.S. Koyanagi, W.I. Leung, and D.M. Olson, Hyperoxia increases protein mass of 5-lipoxygenase and its activating protein, flap, and leukotriene B(4) output in newborn rat lungs. Exp Lung Res, 2002. 28(8): p. 671-84.
Olson, D.M., J.E. Mijovic, D.B. Zaragoza, and J.L. Cook, Prostaglandin endoperoxide H synthase type 1 and type 2 messenger ribonucleic acid in human fetal tissues throughout gestation and in the newborn infant. Am J Obstet Gynecol, 2001. 184(2): p. 169-74.
Manji, J.S., C.J. O'Kelly, W.I. Leung, and D.M. Olson, Timing of hyperoxic exposure during alveolarization influences damage mediated by leukotrienes. Am J Physiol Lung Cell Mol Physiol, 2001. 281(4): p. L799-806.
Xiong, X., F.L. Wang, S.T. Davidge, N.N. Demianczuk, D.C. Mayes, D.M. Olson, and L.D. Saunders, Maternal smoking and preeclampsia. J Reprod Med, 2000. 45(9): p. 727-32.
Mijovic, J.E., N. Demianczuk, D.M. Olson, and T. Zakar, Prostaglandin endoperoxide H synthase mRNA 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 labour. Bjog, 2000. 107(2): p. 267-73.
Cook, J.L., D.B. Zaragoza, D.H. Sung, and D.M. Olson, Expression of myometrial activation and stimulation genes in a mouse model of preterm labor: myometrial activation, stimulation, and preterm labor. Endocrinology, 2000. 141(5): p. 1718-28.
Zakar, T., J.E. Mijovic, D. Bhardwaj, and D.M. Olson, Tyrosine kinase inhibitors block the glucocorticoid stimulation of prostaglandin endoperoxide H synthase expression in amnion cells. Can J Physiol Pharmacol, 1999. 77(2): p. 138-42.
Xiong, X., D. Mayes, N. Demianczuk, D.M. Olson, S.T. Davidge, C. Newburn-Cook, and L.D. Saunders, Impact of pregnancy-induced hypertension on fetal growth. Am J Obstet Gynecol, 1999. 180(1 Pt 1): p. 207-13.
Mijovic, J.E., T. Zakar, J. Angelova, and D.M. Olson, Prostaglandin endoperoxide H synthase mRNA expression in the human amnion and decidua during pregnancy and in the amnion at preterm labour. Mol Hum Reprod, 1999. 5(2): p. 182-7.
Cook, J.L., D.B. Zaragoza, N.M. White, C.L. Randall, and D.M. Olson, Progesterone and prostaglandin H synthase-2 involvement in alcohol-induced preterm birth in mice. Alcohol Clin Exp Res, 1999. 23(11): p. 1793-800.