Quantitative and computational characterization of oxytocin receptor signaling: Administrative supplement

催产素受体信号传导的定量和计算表征:行政补充

基本信息

  • 批准号:
    10175765
  • 负责人:
  • 金额:
    $ 27.95万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-08-19 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

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.
项目摘要 在美国,近一半的孕妇接受了一种合成的神经肽催产素治疗, 引产或增加分娩或预防产后出血。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力。此外,催产素受体(OXTR)可以 在长期催产素给药后停止对催产素反应(变得脱敏),通常导致 需要剖腹产。OXTR激活的失败可导致大量的母体发病率,并且在极端情况下, 例,因产后出血死亡。我们的长期目标是制定改善OXTR的策略 从而提高孕妇的安全性。在我们的研究中,我们假设 OXTR遗传变异导致了观察到的对催产素的个体反应差异, 建议量化这些影响,以建立一个能够预测反应的计算模型。在这 作为补充,我们提出了通过鉴定和 表征OXTR阳性变构调节剂(PAMS)。OXTR PAM将是理想的治疗剂,因为 它们在没有激动剂的情况下不激活它们的靶受体。相反,它们增强内源性配体 通过与天然配体结合位点之外的受体结合来产生活性。因此,OXTR PAM将 主要增强子宫中的OXTR激活,其中催产素浓度最高,并遵循 与分娩期间催产素脉冲释放所引起的相同的时间OXTR激活模式。我们将奉行 两个具体目的:1)鉴定和验证OXTR的正向别构调节剂,和2)确定 热门化合物增强OXTR信号传导。为了识别PAM,我们将进行大规模筛选 不同的小分子化合物。在表征PAM对OXTR信号传导的影响时,我们还将获得 定量数据来增强我们的计算方法。总的来说,来自受资助的R01的数据和 补充将导致个体化催产素给药和替代药理学方法, 激活OXTR以诱导或增加分娩。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Sarah K. England其他文献

Diet Quality in Pregnancy and the Risk of Fetal Growth Restriction
  • DOI:
    10.1016/j.ajog.2021.11.081
  • 发表时间:
    2022-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Xiao Yu Wang;Peinan Zhao;Antonina I. Frolova;Anthony O. Odibo;Ebony B. Carter;Jeannie C. Kelly;Sarah K. England;Nandini Raghuraman
  • 通讯作者:
    Nandini Raghuraman
The association between first trimester physical activity levels and perinatal outcomes
孕早期身体活动水平与围产期结局之间的关联
  • DOI:
    10.1016/j.ajogmf.2024.101534
  • 发表时间:
    2024-12-01
  • 期刊:
  • 影响因子:
    3.100
  • 作者:
    Virginia Y. Watkins;Peinan Zhao;Antonina I. Frolova;Ebony B. Carter;Jeannie C. Kelly;Anthony O. Odibo;Sarah K. England;Nandini Raghuraman
  • 通讯作者:
    Nandini Raghuraman
800: Area deprivation index and adverse obstetric outcomes
  • DOI:
    10.1016/j.ajog.2019.11.815
  • 发表时间:
    2020-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Molly J. Stout;Megan C. Oakes;Jessica Chubiz;Olivia Passafiume;Anjana Delhi;Candice Woolfolk;Emily Jungheim;Sarah K. England;George A. Macones;Methodius G. Tuuli
  • 通讯作者:
    Methodius G. Tuuli
Sleep variability and time to achieving pregnancy: findings from a pilot cohort study of women desiring pregnancy
睡眠变异性与受孕时间:一项针对渴望怀孕女性的试点队列研究结果
  • DOI:
    10.1016/j.fertnstert.2025.01.019
  • 发表时间:
    2025-07-01
  • 期刊:
  • 影响因子:
    7.000
  • 作者:
    Peinan Zhao;Emily S. Jungheim;Bronwyn S. Bedrick;Leping Wan;Patricia T. Jimenez;Ronald McCarthy;Jessica Chubiz;Justin C. Fay;Erik D. Herzog;Siobhan Sutcliffe;Sarah K. England
  • 通讯作者:
    Sarah K. England
1125: First trimester stress and depression as risk factors for preterm birth
  • DOI:
    10.1016/j.ajog.2019.11.1137
  • 发表时间:
    2020-01-01
  • 期刊:
  • 影响因子:
  • 作者:
    Megan C. Oakes;Jessica Chubiz;Olivia Passafiume;Bronwyn Bedrick;Sarah K. England;George A. Macones;Methodius G. Tuuli;Emily Jungheim;Molly J. Stout
  • 通讯作者:
    Molly J. Stout

Sarah K. England的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Sarah K. England', 18)}}的其他基金

Quantitative and computational characterization of oxytocin receptor signaling
催产素受体信号传导的定量和计算表征
  • 批准号:
    10428510
  • 财政年份:
    2019
  • 资助金额:
    $ 27.95万
  • 项目类别:
Quantitative and computational characterization of oxytocin receptor signaling
催产素受体信号传导的定量和计算表征
  • 批准号:
    10206215
  • 财政年份:
    2019
  • 资助金额:
    $ 27.95万
  • 项目类别:
Quantitative and computational characterization of oxytocin receptor signaling
催产素受体信号传导的定量和计算表征
  • 批准号:
    10636923
  • 财政年份:
    2019
  • 资助金额:
    $ 27.95万
  • 项目类别:
A novel molecular mechanism for stimulating uterine contractility by oxytocin
催产素刺激子宫收缩的新分子机制
  • 批准号:
    10539176
  • 财政年份:
    2016
  • 资助金额:
    $ 27.95万
  • 项目类别:
A NOVEL MOLECULAR MECHANISM FOR STIMULATING UTERINE CONTRACTILITY BY OXYTOCIN
催产素刺激子宫收缩的新型分子机制
  • 批准号:
    9251837
  • 财政年份:
    2016
  • 资助金额:
    $ 27.95万
  • 项目类别:
A novel molecular mechanism for stimulating uterine contractility by oxytocin
催产素刺激子宫收缩的新分子机制
  • 批准号:
    10703507
  • 财政年份:
    2016
  • 资助金额:
    $ 27.95万
  • 项目类别:
NOVEL MECHANISMS OF OXYTOCIN ACTION
催产素作用的新机制
  • 批准号:
    8697084
  • 财政年份:
    2013
  • 资助金额:
    $ 27.95万
  • 项目类别:
NOVEL MECHANISMS OF OXYTOCIN ACTION
催产素作用的新机制
  • 批准号:
    8543851
  • 财政年份:
    2013
  • 资助金额:
    $ 27.95万
  • 项目类别:
THE ROLE OF THE BKCA CHANNEL IN THE REGULATION OF UTERINE EXCITABILITY
BKCA 通道在子宫兴奋性调节中的作用
  • 批准号:
    7604805
  • 财政年份:
    2007
  • 资助金额:
    $ 27.95万
  • 项目类别:
THE ROLE OF THE BKCA CHANNEL IN THE REGULATION OF UTERINE EXCITABILITY
BKCA 通道在子宫兴奋性调节中的作用
  • 批准号:
    7376987
  • 财政年份:
    2006
  • 资助金额:
    $ 27.95万
  • 项目类别:

相似国自然基金

Agonist-GPR119-Gs复合物的结构生物学研究
  • 批准号:
    32000851
  • 批准年份:
    2020
  • 资助金额:
    24.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

S1PR1 agonistによる脳血液関門制御を介した脳梗塞の新規治療法開発
S1PR1激动剂调节血脑屏障治疗脑梗塞新方法的开发
  • 批准号:
    24K12256
  • 财政年份:
    2024
  • 资助金额:
    $ 27.95万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
AHR agonistによるSLE皮疹の新たな治療薬の開発
使用 AHR 激动剂开发治疗 SLE 皮疹的新疗法
  • 批准号:
    24K19176
  • 财政年份:
    2024
  • 资助金额:
    $ 27.95万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
Evaluation of a specific LXR/PPAR agonist for treatment of Alzheimer's disease
特定 LXR/PPAR 激动剂治疗阿尔茨海默病的评估
  • 批准号:
    10578068
  • 财政年份:
    2023
  • 资助金额:
    $ 27.95万
  • 项目类别:
AUGMENTING THE QUALITY AND DURATION OF THE IMMUNE RESPONSE WITH A NOVEL TLR2 AGONIST-ALUMINUM COMBINATION ADJUVANT
使用新型 TLR2 激动剂-铝组合佐剂增强免疫反应的质量和持续时间
  • 批准号:
    10933287
  • 财政年份:
    2023
  • 资助金额:
    $ 27.95万
  • 项目类别:
Targeting breast cancer microenvironment with small molecule agonist of relaxin receptor
用松弛素受体小分子激动剂靶向乳腺癌微环境
  • 批准号:
    10650593
  • 财政年份:
    2023
  • 资助金额:
    $ 27.95万
  • 项目类别:
AMPKa agonist in attenuating CPT1A inhibition and alcoholic chronic pancreatitis
AMPKa 激动剂减轻 CPT1A 抑制和酒精性慢性胰腺炎
  • 批准号:
    10649275
  • 财政年份:
    2023
  • 资助金额:
    $ 27.95万
  • 项目类别:
Investigating mechanisms underpinning outcomes in people on opioid agonist treatment for OUD: Disentangling sleep and circadian rhythm influences on craving and emotion regulation
研究阿片类激动剂治疗 OUD 患者结果的机制:解开睡眠和昼夜节律对渴望和情绪调节的影响
  • 批准号:
    10784209
  • 财政年份:
    2023
  • 资助金额:
    $ 27.95万
  • 项目类别:
A randomized double-blind placebo controlled Phase 1 SAD study in male and female healthy volunteers to assess safety, pharmacokinetics, and transient biomarker changes by the ABCA1 agonist CS6253
在男性和女性健康志愿者中进行的一项随机双盲安慰剂对照 1 期 SAD 研究,旨在评估 ABCA1 激动剂 CS6253 的安全性、药代动力学和短暂生物标志物变化
  • 批准号:
    10734158
  • 财政年份:
    2023
  • 资助金额:
    $ 27.95万
  • 项目类别:
A novel nanobody-based agonist-redirected checkpoint (ARC) molecule, aPD1-Fc-OX40L, for cancer immunotherapy
一种基于纳米抗体的新型激动剂重定向检查点 (ARC) 分子 aPD1-Fc-OX40L,用于癌症免疫治疗
  • 批准号:
    10580259
  • 财政年份:
    2023
  • 资助金额:
    $ 27.95万
  • 项目类别:
Fentanyl Addiction: Individual Differences, Neural Circuitry, and Treatment with a GLP-1 Receptor Agonist
芬太尼成瘾:个体差异、神经回路和 GLP-1 受体激动剂治疗
  • 批准号:
    10534864
  • 财政年份:
    2023
  • 资助金额:
    $ 27.95万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了