Role of GRK6-Mediated Oxytocin Receptor Desensitization in Labor

GRK6 介导的催产素受体脱敏在分娩中的作用

• 批准号: 8372535
• 负责人: Chad A Grotegut
• 金额: $ 12.84万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8372535
• 关键词: Affect; Agonist; Arrestins; Award; Basic Science; Bathing; Binding; Biology; Birth; Calcium Signaling; Cell membrane; Cessation of life; Chad; Clinical; Clinical Investigator Award; Country; Cytoplasm; Data; Detection; Development; Ensure; Etiology; Event; Exhibits; Failure; Family; Female; Fetus; Foundations; Frequencies; Future; G protein coupled receptor kinase; G-Protein-Coupled Receptors; GRK; GRK6 gene; GTP-Binding Proteins; Gene Deletion; Goals; Heterozygote; Hypoxia; In Vitro; Induced Labor; Infusion procedures; Knockout Mice; Lead; Length; Life; Live Birth; Mediating; Mediation; Mediator of activation protein; Mentors; Modeling; Molecular; Monitor; Mus; Myometrial; Organ; Outcome; Oxygen; Oxytocin; Oxytocin Receptor; Partner in relationship; Patients; Pattern; Perfusion; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Postpartum Hemorrhage; Postpartum Period; Pregnancy; Prevention; Protocols documentation; Receptor Activation; Receptor Signaling; Recruitment Activity; Regulation; Relaxation; Research; Research Personnel; Risk; Role; Scaffolding Protein; Scientist; Secondary to; Signal Transduction; Techniques; Testing; Tissues; Training; Training Programs; Transgenic Mice; United States; Uterine Contraction; Uterine Inertia; Uterus; Wild Type Mouse; Woman; Women' s Health; Work; abstracting; base; beta-arrestin; career; desensitization; experience; fetal; fetus hypoxia; implantable device; improved; in vivo; innovation; intrapartum; male; member; myometrium; overexpression; pregnant; pressure; prevent; pup; receptor; receptor internalization; reproductive; response; skills; stillbirth; tool; uterine contractility

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.

描述（由申请人提供）：项目摘要/摘要候选人（乍得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。K 08指导临床科学家研究生涯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，使实质性的科学发现，将改善妇女的健康。通过K 08计划，我将获得成为一名成功的独立调查员的技能和经验。题目：在这个国家，引产率从1990年的每100个活产9.5个增加到每100个活产22.3个 2005年出生。随着引产率的提高，越来越多的妇女可能会接受长时间的催产素注射。持续催产素输注导致催产素受体脱敏，临床上可表现为功能失调性分娩或分娩后子宫收缩乏力。这些事件分别增加了剖宫产或产后出血的风险。了解催产素受体脱敏的分子机制是开发预防催产素受体脱敏和这些不良临床事件的方案或药物的重要一步。计划：该K 08提出利用一种创新技术，该技术能够监测子宫收缩的强度和频率，以及缺乏GRK 6（催产素受体脱敏的重要介质）的小鼠模型的分娩持续时间。缺乏GRK 6的雌性小鼠具有生殖表型，因为它们产生死产的足月、适当生长的小鼠。我们认为，这种表型是继发于分娩过程中催产素受体脱敏的缺乏，产生长时间的强直性收缩，减少分娩过程中向幼崽输送的氧气。这个K 08的提议将检验缺乏GRK 6的小鼠由于缺乏催产素受体脱敏而表现出更强的子宫收缩和更短的分娩持续时间的假设。将缺乏GRK 6的子宫肌条悬挂在组织器官浴中，并测定它们对催产素脱敏方案的反应（目的1）。GRK 6在自发和催产素诱导的分娩中的作用将使用缺乏GRK 6的活孕小鼠进行测试，所述小鼠具有植入子宫中的动态压力装置，其能够检测子宫收缩强度、频率和分娩持续时间。使用检测缺氧的工具，我们将确定分娩期间经历的胎儿缺氧是否是缺乏GRK 6的妊娠小鼠中观察到的死胎的病因（目的2）。最后，我们将创建一个转基因小鼠，在子宫中过度表达GRK 6，产生一个表型的夸张催产素受体脱敏（目标3）。科学提案和建议的导师团队将确保实现本K 08的目标。 公共卫生关系：相关性引产在美国很常见，但使妇女暴露于长期催产素输注的可能性，导致催产素受体脱敏，这是功能障碍性分娩和子宫收缩乏力的重要介质。该K 08将探索GRK 6介导的催产素受体脱敏在分娩过程中的生理效应，为未来开发非脱敏催产素受体激动剂提供基础。