Oxytocin is used to induce or augment labor in about half of patients (2 million per year) who deliver in US hospitals. The oxytocin dose required to induce labor varies about 20-fold between individuals, with some patients requiring high doses of oxytocin that have been linked to both maternal and fetal complications. To avoid these adverse effects, obstetricians need to be able to predict each individual's oxytocin dose requirement and tailor their approach to labor management accordingly. Previous studies suggest that genetic variations in the oxytocin receptor (OXTR) gene contribute to the vast variation in oxytocin dose requirement, but the mechanisms by which these variants act are unknown. The proposed research elucidates the effects of both rare missense single nucleotide variants (mSNVs) and common noncoding single nucleotide polymorphisms (SNPs) on OXTR function and expression and on uterine response to oxytocin.
Aim 1 of this proposal investigates the hypothesis that OXTR mSNVs identified in individuals who responded to high or low doses of oxytocin modulate OXTR's ligand binding and signaling capabilities.
This aim will examine the effect of mSNVs on OXTR's ability to bind oxytocin, to recruit its signaling partners ?-arrestin and Gq, and to potentiate key pro-labor signaling pathways.
Aim 2 investigates the hypothesis that noncoding SNPs in OXTR alter OXTR expression and thereby modulate uterine sensitivity to oxytocin. Analysis of allele-specific OXTR expression will be used to identify functional SNPs that may modulate OXTR expression. Finally, this Aim will determine the effects of OXTR SNPs and variations in OXTR expression on oxytocin response in myometrial cells from patient samples. In the long term, the proposed work will aid the development of individualized approaches for labor management that will minimize the risk of oxytocin overdose and the ensuing potentially fatal outcomes. The candidate has assembled a multidisciplinary mentorship team, led by sponsor Dr. Sarah England, that will ground her training in the study of uterine physiology, genetics, and clinical and translational science. The candidate's institution, Washington University School of Medicine, has a long history of supporting MD-PhD students and physician-scientists at all stages of their training. By conducting this research, the candidate will acquire valuable research experience that will help her become an independent physician-scientist working to translate findings from genetic studies to functional impacts on physiology and human health.
Completion of these aims will suggest the mechanisms by which genetic variants in the oxytocin receptor (OXTR) gene contribute to the large variation in oxytocin responsiveness between patients. The findings from this study may suggest that OXTR sequencing, genotyping, or expression analysis would be useful to identify individuals likely to respond or fail to respond to safe doses of oxytocin. Personalizing approaches to inducing labor would increase the safety of oxytocin use and potentially reduce maternal morbidity and mortality.
