Role of GRK6-Mediated Oxytocin Receptor Desensitization in Labor

描述(由申请人提供)：项目摘要/摘要候选人(查德·A·格罗特古特，医学博士)：我的长期目标是通过在分娩过程中进行创新的、与患者相关的研究来改善妇女及其家庭的生活，以改善怀孕和分娩结果。为了实现这些目标，我组建了一支优秀的导师团队，并制定了一项特殊的培训计划，这将建立在我坚实的临床基础上。K08指导临床科学家研究职业奖将为我提供基本的基础科学培训，这将增强我强大的临床背景，做出实质性的科学发现，改善女性的健康。有了K08项目，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名活产9.5人增加到每100名活产22.3人 2005年出生人数。随着引产率的增加，接受长时间输注催产素的女性数量增加的可能性也随之增加。持续输注催产素会导致催产素受体脱敏，临床上可表现为分娩功能障碍或分娩后子宫无力。这些事件分别增加了剖腹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步骤。计划：K08建议利用一种创新的技术，在缺乏GRK6的小鼠模型中监测子宫收缩的强度和频率，以及分娩持续时间，GRK6是催产素受体脱敏的基本介质。缺乏GRK6的雌性小鼠具有生殖表型，因为它们生产的是足月、适当发育的死胎小鼠。我们认为，这种表型继发于分娩期间没有催产素受体脱敏，导致持续的强直性收缩，减少分娩期间对幼鼠的氧气输送。这项K08提案将检验这样一种假设，即由于缺乏催产素受体脱敏作用，缺乏GRK6的小鼠将表现出更强的子宫收缩和更短的产程。将缺乏GRK6的子宫肌条悬挂在组织器官浴中，并测定其对催产素脱敏方案的反应(目标1)。GRK6在自然分娩和催产素引产中的作用将在缺乏GRK6的活体怀孕小鼠身上进行测试，这些小鼠在子宫中植入了一个动态压力装置，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，我们将确定分娩过程中经历的胎儿缺氧是否是缺乏GRK6的怀孕小鼠死产的原因(目标2)。最后，我们将创造一个在子宫中过度表达GRK6的转基因小鼠，以产生夸大的催产素受体脱敏表型(目标3)。科学建议和建议的导师团队将确保实现本次K08的目标。

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.