Candidate (Chad A. Grotegut, MD): My long-term goal is to improve the lives of women and their families by conducting innovative, patient-relevant research in parturition to improve pregnancy and labor outcomes. To achieve these goals, I have assembled an outstanding mentor team and developed an exceptional training program that will build upon my strong clinical foundation. The K08 Mentored Clinical Scientist Research Career Award will provide me with the essential basic science training that will augment my strong clinical background, to make substantial scientific discoveries that will improve women's health. With the K08 program, I will obtain the skills and experience to become a successful independent investigator. Topic: In this country, the rate of labor induction has increased from 9.5 per 100 live births in 1990 to 22.3 per 100 live births in 2005. With increasing labor induction rates comes the likelihood of increased numbers of women receiving prolonged oxytocin infusions. Continuous oxytocin infusions lead to oxytocin receptor desensitization that clinically can present as both dysfunctional labor or as uterine atony following delivery. These events increase the risk for cesarean delivery or postpartum hemorrhage, respectively. Understanding the molecular mechanism of oxytocin receptor desensitization is an important step in developing protocols or agents to prevent oxytocin receptor desensitization and these adverse clinical events. Plan: This K08 proposes to utilize an innovative technique that enables the monitoring of strength and frequency of uterine contraction, and duration of labor in murine models lacking GRK6, an essential mediator of oxytocin receptor desensitization. Female mice lacking GRK6 have a reproductive phenotype in that they deliver full-term, appropriately grown mice that are stillborn. We propose that this phenotype is secondary to absence of oxytocin receptor desensitization during labor, producing prolonged, tetanic contractions, decreasing oxygen delivery to the pups during labor. This K08 proposal will test the hypothesis that mice lacking GRK6 will exhibit stronger uterine contractions and shorter duration of labor due to absence of oxytocin receptor desensitization. Uterine muscle strips lacking GRK6 with be hung in a tissue organ bath and their response to an oxytocin desensitization protocol determined (Aim 1). The role of GRK6 in spontaneous and oxytocin-induced labor will be tested using live pregnant mice lacking GRK6 who have an ambulatory pressure device implanted into the uterus that enables the detection of uterine contraction strength, frequency, and duration of labor. Using a tool that detects for hypoxia, we will determine if fetal hypoxia experienced during labor is the etiology of stillbirth seen in pregnant mice lacking GRK6 (Aim 2). Lastly, we will create a transgenic mouse that over expresses GRK6 in the uterus to produce a phenotype of exaggerated oxytocin receptor desensitization (Aim 3). The scientific proposal and the proposed mentor team will ensure that the goals of this K08 are achieved.
Relevance Labor induction is common in the United States but exposes women to the potential for prolonged oxytocin infusions resulting in oxytocin receptor desensitization, an important mediator of dysfunctional labor and uterine atony. This K08 will explore the physiologic effects of GRK6-mediated oxytocin receptor desensitization during parturition, providing the foundation for future development of non-desensitizing oxytocin receptor agonists.
|Grotegut, Chad A; Mao, Lan; Pierce, Stephanie L et al. (2016) Enhanced Uterine Contractility and Stillbirth in Mice Lacking G Protein-Coupled Receptor Kinase 6 (GRK6): Implications for Oxytocin Receptor Desensitization. Mol Endocrinol 30:455-68|