My primary interest is the study of preterm birth with the intention of decreasing its rate and improving pregnancy outcomes. Preterm birth is the single most important problem in perinatal health, leading to perinatal mortality and morbidity and life-long adverse health and social consequences. Alberta has the highest provincial rate in Canada and everywhere rates are rising. My commitments to studying this problem and hopefully contributing to its improvement are summarized below.
1. I co-established in 2007-08 the interdisciplinary, international research team, Preterm Birth and Healthy Outcomes Team (PreHOT, www.prehot.org), funded by Alberta Innovates Health Solutions. Originally it had 22 investigators who addressed the problem from a broad perspective including a strong laboratory team addressing basic science issues. The Team created a birth cohort (All Our Babies) of 1800 mothers and infants, established three active companies, identified the earliest known events and new events in the birth cascade along with new targets for intervention, and developed new diagnostic approaches to assess preterm birth risk and new therapies to delay preterm birth and prolong pregnancy.
2. In 2011-2012 I founded three active companies to develop and commercialize our laboratory and Team discoveries. The first, PremGen Diagnostics, Inc., develops methods to assess preterm birth risk in women using genomic, psychological and environmental data. In this instance, these approaches are targeted towards non-pregnant women or those in early pregnancy with the intent to stratify them into high risk and low risk groups. Livmor Diagnostics, Inc. is developing a novel leukocyte activation test that assesses acute risk of preterm birth (within 1-2 weeks) in high-risk pregnant women. This test can also be used to monitor a patient’s response to treatment for preterm birth. It will result in a paradigm change in the approach for developing new drugs for preterm birth. The third company, Maternica Therapeutics, Inc., is developing new small peptide allosteric receptor antagonists that target the birth cascade at all levels with the intent to delay preterm birth and prolong pregnancy. We are working closely with University of Montreal collaborators in this program. We are working closely with TEC Edmonton and Biocatalyst 4 Development to manage these companies and bring our products to the FDA testing level.
3. In new studies, PhD candidate, Dr. Inge Christiaens, and I are exploring gene-environment interactions that associate with preterm birth. We are seeking correlations between maternal perceived chronic stress (environmental factor) and maternal single nucleotide polymorphisms (SNPs) (genetic factor) and preterm birth. Dr. Christiaens has found that two or more childhood traumatic events associate with preterm birth. This study should inform us whether a gene-environment interaction indicates a higher risk for preterm birth.
4. With an international group of scientists led by PreHOT member, Craig Pennell, 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 < 10-8) in similar cohorts of women around the world, including our Edmonton cohort. We have filed a provisional patent for the signature. The intention is to in-license this to PremGen to develop it further. Current work involves a new international team of geneticists and genomics experts I co-direct exploring further preterm birth prediction and assigning genomic signatures to child development.
5. Former post-doctoral fellows, Dr. Nardhy Gomez-Lopez (Assistant Professor at Wayne State University) and Dr. Satomi Tanaka of Juntendo Medical University, Tokyo, have identified the earliest events in the birth cascade. These involve peripheral leukocyte activation and precede uterine activation for labour. We have filed a patent applicaton for a prognostic test that uses activated peripheral blood leukocytes as predictors of preterm birth risk in pregnant women. Post-doctoral fellows, Dr. Tomohito Ishiguro and Dr. Jun Takeda are continuing this important work in rodent and human studies.
6. With Drs. Sylvain Chemtob and William Lubell (U of Montreal) we are studying (with Dr. Gerlinde Metz, University of Lethbridge) the mechanism of action of allosteric peptide receptor inhibitors that delay preterm birth in mice and term delivery in mice. These drugs can be administered via several means, can be used prophylactically and are extremely inexpensive to manufacture.
7. I collaborate with Professor Xin Ni, the Chair of Physiology at the Second Military Medical University in Shanghai and with Drs. Donna Slater and Stephen Wood of the University of Calgary and Dr. Bryan F. Mitchell of the University of Alberta. We share a joint China-CIHR grant to study the interaction of PGF2a and corticotrophin releasing hormone (CRH) on the activation and contractile apparatus of human myometrial cells. Ms. Chen (Debbie) Xu from Professor Ni’s laboratory worked on her Ph.D. thesis in my laboratory. Ms. Xu has discovered new roles for prostaglandins in activating the uterus for labour and in releasing chemokines and cytokines. It suggests that prostaglandins are working more ‘upstream’ than we previously thought.
8. We are further defining the role of the prostaglandin (PG) F2a receptor (FP) in the control of human myometrial smooth muscle cells with Dr. Sylvain Chemtob and his colleagues and with graduate student Kelycia Leimert. More specific information on the mechanism of PGF2a action with its receptor and intracellular pathways should be revealed. We sequenced for the first time the human and mouse FP promoters and have identified repressor and activator sequences. This information helps us study the regulation of FP in cultured human myometrial cells. Both interleukin (IL)-6 and IL-1b stimulate FP expression and IL-1b does so via an NFkB mechanism. Forskolin activation of adenylate cyclase also increases FP mRNA expression and does so via a protein kinase a pathway and a MAP kinase kinase pathway. The ligand, PGF2a, stimulates receptor internalization and suppresses FP mRNA expression via protein kinase C. Interleukin (IL)-1b stimulates FP expression and we feel at term maintains its levels to facilitate its activating and contracting role in parturition.
9. In collaboration with Dr. Sarah Robertson (U of Adelaide) we found that interleukin (IL)-6 knockout mice deliver one day late, due in part to absent or attenuated increases in FP and oxytocin receptor mRNA. We are using her knock-out models and the allosteric peptide antagonists devised by Drs. Lubell and Chemtob to examine the roles of cytokines in the birth pathway in mice. Future work will include studying the role of TLR4 and inflammasome assembly with new peptide antagonists.
10. Other collaborations with Dr. Gerlinde Metz of the University of Lethbridge include the development of a stressed rat model for preterm delivery. Her studies have found that the daughters and granddaughters of pregnant rats stressed during their pregnancies deliver their pups earlier than control, non-stressed dams. Interestingly, these dams pass on to their daughters and granddaughters considerable adverse behaviours via epigenetic mechanisms as we have learned by collaborating with Dr. Igor Kovalchuk (U of Lethbridge, Director of the Alberta Epigenetic Institute).
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