Quantitative and computational characterization of oxytocin receptor signaling: Administrative supplement

项目总结 在美国，近一半的孕妇接受合成版本的神经肽催产素治疗，以 引产或增加分娩次数或防止产后出血。然而，女性需要广泛的催产素 剂量，以引起适当程度的子宫收缩。此外，催产素受体(OXTR)可以 在长期服用催产素后停止对催产素的反应(变得脱敏)，通常会导致 需要剖腹产。OXTR激活失败可能会导致大量产妇发病，在极端情况下 产后出血死亡3例。我们的长期目标是制定改进OXTR的策略 提高反应速度，从而提高孕妇的安全性。在我们的父母拨款中，我们假设 OXTR基因变异是导致观察到的催产素和催产素的个体反应差异的原因 建议量化这些影响，以便建立一个能够预测反应的计算模型。在这 作为补充，我们建议开发一种新的方法来调节OXTR活性，方法是识别和 氧X受体正变构调节剂(PAM)的表征。Oxtr PAM将是理想的治疗方法，因为 在没有激动剂的情况下，它们不会激活目标受体。相反，它们能增强内源性配体 通过与天然配体结合部位以外的受体结合而发挥活性。因此，Oxtr PAM将 主要增强催产素浓度最高的子宫中OXTR的激活，并遵循 产程中催产素脉冲性释放所产生的相同的OXTR激活模式。我们将继续追查 两个特定的目标：1)确定和验证OXTR的正变构调节器，以及2)确定 最受欢迎的化合物增强了OXTR信号。为了识别PAM，我们将执行大规模筛查 各种各样的小分子化合物。在表征PAM对OXTR信号的影响时，我们还将获得 量化数据，以增强我们的计算方法。加在一起，来自基金R01和这个的数据 补充催产素将导致个性化的催产素给药和一种替代的药物治疗方法 激活OXTR以诱导或增加分娩。

PROJECT SUMMARY In the US, nearly half of all pregnant women are treated with a synthetic version of the neuropeptide oxytocin to induce or augment labor or prevent postpartum hemorrhage. However, women require a wide range of oxytocin doses to elicit an appropriate degree of uterine contractility. Furthermore, the oxytocin receptor (OXTR) can cease to respond to oxytocin (become desensitized) after long-term oxytocin administration, often leading to the need for cesarean delivery. Failure of OXTR activation can lead to substantial maternal morbidity and, in extreme cases, mortality due to postpartum hemorrhage. Our long-term goal is to develop strategies to improve OXTR responsiveness and thereby improve safety for pregnant women. In our parent grant, we hypothesized that OXTR genetic variants are contributing to the observed differences in individual response to oxytocin and propose to quantitate these effects in order to build a computational model able to predict response. In this supplement, we propose to develop a new approach for regulation of OXTR activity by identifying and characterizing OXTR positive allosteric modulators (PAMs). OXTR PAMs would be ideal therapeutics because they do not activate their target receptor in the absence of an agonist. Instead, they enhance endogenous ligand activity by binding to the receptor outside of the native ligand binding site. Thus, OXTR PAMs would predominantly enhance OXTR activation in the uterus, where oxytocin concentration is highest, and follow the same temporal OXTR activation pattern brought about by pulsatile oxytocin release during labor. We will pursue two Specific Aims: 1) Identify and validate positive allosteric modulators of OXTR, and 2) Determine how the top hit compounds enhance OXTR signaling. In order to identify the PAMs, we will perform a large-scale screen of diverse small-molecule compounds. In characterizing PAM effects on OXTR signaling, we will also obtain quantitative data to enhance our computational approaches. Together, data from the funded R01 and this supplement will lead to individualized oxytocin administration and an alternative pharmacologic approach to activate OXTR to induce or augment labor.