Role of GRK6-Mediated Oxytocin Receptor Desensitization in Labor

项目简介/摘要候选人（Chad A. Grotegut， MD）：我的长期目标是通过开展创新的、与患者相关的分娩研究来改善妇女及其家庭的生活，以改善妊娠和分娩结果。为了实现这些目标，我组建了一个优秀的导师团队，并制定了一个特殊的培训计划，这将建立在我强大的临床基础之上。K08指导临床科学家研究事业奖将为我提供必要的基础科学培训，这将增强我强大的临床背景，使我能够做出实质性的科学发现，改善妇女的健康。通过K08项目，我将获得成为一名成功的独立调查员所需的技能和经验。题目：在这个国家，引产率已经从1990年的每100个活产9.5个增加到每100个活产22.3个

DESCRIPTION (provided by applicant): Project Summary/Abstract 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. PUBLIC HEALTH RELEVANCE: 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.