Multimodal Analysis of Gestational Health and Placental Injury in Opioid-Affected Pregnancies

阿片类药物影响妊娠的妊娠健康和胎盘损伤的多模态分析

基本信息

项目摘要

PROJECT SUMMARY Opioids are medically used for safe pain relief and management. However, illicit opioid use has substantially increased across the US in the past decade, with further worsening during the COVID-19 pandemic, leading to a profound impact on human health. Specifically, opioid use disorder (OUD) during pregnancy poses an increased risk of pregnancy-associated maternal morbidity and mortality, fetal growth restriction (FGR) and related complications, neonatal opioid withdrawal syndrome, and long-term neurobehavioral effects. Some of these risks persist despite the use of safer opioids, such as buprenorphine and methadone, medications for OUD (MOUD) patients. Whereas current studies center mainly on transplacental opioid transport to the fetus and the adverse effects of opioids on infants, the direct impact of illicit and prescription opioids on placental development, differentiation, and function are largely unexplored. The placental floating villi mediate maternal- fetal gas exchange, nutrient uptake, waste release immune defense and the production of hormones and extracellular vesicles (EVs). These villi are covered by a layer of multinucleated, terminally differentiated syncytiotrophoblasts (STBs), which forms the feto-placental frontline that is directly exposed to opioids in the maternal blood. Subjacent to this layer are mononucleated, progenitor cytotrophoblasts (CTBs), which replenish the STB layer through the process of differentiation and fusion. Importantly, injuries to the STB and CTB layers are implicated in pregnancy-associated complications, including FGR and stillbirth. Here we seek to investigate opioid-dependent placental injury, focusing on the most critical and unique layer of placental trophoblasts. We will enroll participants with OUD, including illicit opioids and MOUD (buprenorphine, methadone), examine their pregnancy course and their children’s health through the first year postpartum. Using biospecimens from each participant, including maternal plasma and urine across the three trimesters, placental biopsies and fetal cord blood at delivery, we will employ multimodal cutting-edge technologies, including single-cell RNAseq, spatial transcriptomics, protein chip cytometry and placenta EV RNA profiling, and explore the molecular and cellular processes affected by opioids in the maternal-placental-fetal trio- ecosystem. To gain mechanistic insights into the functional changes in gene expression and EV cargo, we will use an array of model systems, including human trophoblast stem cells and cultured primary human trophoblasts, and mechanistically interrogate pathways underlying opioid injury. We will further correlate key molecular signatures with clinical assessment, including maternal gestational disorders, perinatal and infant neurodevelopmental outcomes. Together, our strategic plan, bolstered by our transdisciplinary team, enables us to address critically important knowledge gaps related to human placenta biology in opioid-affected pregnancies.
项目摘要 阿片类药物在医学上用于安全的疼痛缓解和管理。然而,非法阿片类药物的使用 在过去十年中,美国各地的疫情有所增加,在COVID-19大流行期间进一步恶化,导致 对人类健康产生深远影响。具体而言,妊娠期间的阿片类药物使用障碍(OUD) 与妊娠相关的孕产妇发病率和死亡率风险增加,胎儿生长受限(FGR), 相关并发症、新生儿阿片类戒断综合征和长期神经行为影响。一些 尽管使用更安全的阿片类药物,如丁丙诺啡和美沙酮,这些风险仍然存在, OUD(MOUD)患者。而目前的研究主要集中在阿片类药物经胎盘转运到胎儿 以及阿片类药物对婴儿的不良影响,非法和处方阿片类药物对胎盘的直接影响, 发育、分化和功能在很大程度上尚未探索。胎盘漂浮绒毛介导母体- 胎儿气体交换,营养吸收,废物释放免疫防御和激素的产生, 细胞外囊泡(EV)。这些绒毛被一层多核的、终末分化的 合胞体滋养层细胞(STBs),形成胎儿-胎盘前线,直接暴露于阿片类药物, 母亲的血在这一层下面是单核的祖细胞滋养层(CTB), 通过分化融合的过程补充STB层。重要的是,STB的受伤, CTB层与妊娠相关的并发症有关,包括FGR和死胎。在这里我们寻求 研究阿片类药物依赖性胎盘损伤,重点是胎盘最关键和独特的一层, 滋养层我们将招募OUD参与者,包括非法阿片类药物和MOUD(丁丙诺啡, 检查她们的怀孕过程及产后第一年的子女健康情况。 使用每个参与者的生物样本,包括三个孕期的母体血浆和尿液, 胎盘活检和分娩时的胎儿脐带血,我们将采用多模式尖端技术, 包括单细胞RNAseq、空间转录组学、蛋白芯片细胞术和胎盘EV RNA分析, 并探索母体-胎盘-胎儿三重体中阿片类药物影响的分子和细胞过程, 生态系统为了获得对基因表达和EV货物功能变化的机制见解,我们将 使用一系列模型系统,包括人滋养层干细胞和培养的原代人 滋养层,并机械地询问阿片损伤的潜在途径。我们将进一步关联关键 临床评估的分子特征,包括孕产妇妊娠期疾病、围产期和婴儿 神经发育结果。我们的战略计划,在我们跨学科团队的支持下, 我们将解决与受阿片类药物影响的人类胎盘生物学相关的至关重要的知识差距 怀孕。

项目成果

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Elizabeth E Krans其他文献

Elizabeth E Krans的其他文献

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{{ truncateString('Elizabeth E Krans', 18)}}的其他基金

Improving Postpartum Contraceptive Decision-Making Among Women With Substance Use Disorders
改善患有药物使用障碍的女性的产后避孕决策
  • 批准号:
    10211810
  • 财政年份:
    2021
  • 资助金额:
    $ 309.22万
  • 项目类别:
Improving Postpartum Contraceptive Decision-Making Among Women With Substance Use Disorders
改善患有药物使用障碍的女性的产后避孕决策
  • 批准号:
    10594574
  • 财政年份:
    2021
  • 资助金额:
    $ 309.22万
  • 项目类别:
Improving Postpartum Contraceptive Decision-Making Among Women With Substance Use Disorders
改善患有药物使用障碍的女性的产后避孕决策
  • 批准号:
    10408727
  • 财政年份:
    2021
  • 资助金额:
    $ 309.22万
  • 项目类别:
2/4: Investigation of Opioid Exposure and Neurodevelopment (iOPEN)
2/4:阿片类药物暴露和神经发育的调查 (iOPEN)
  • 批准号:
    9898919
  • 财政年份:
    2019
  • 资助金额:
    $ 309.22万
  • 项目类别:
2/4: Investigation of Opioid Exposure and Neurodevelopment (iOPEN)
2/4:阿片类药物暴露和神经发育的调查 (iOPEN)
  • 批准号:
    10019149
  • 财政年份:
    2019
  • 资助金额:
    $ 309.22万
  • 项目类别:
Buprenorphine Assignment in Pregnancy: Objective Criteria
妊娠期丁丙诺啡分配:客观标准
  • 批准号:
    9034137
  • 财政年份:
    2016
  • 资助金额:
    $ 309.22万
  • 项目类别:
Facilitating HCV Treatment through Tailored Prenatal Care for HCV Infected, Substance using Pregnant Women
通过为 HCV 感染者和使用药物的孕妇提供定制的产前护理来促进 HCV 治疗
  • 批准号:
    9053467
  • 财政年份:
    2015
  • 资助金额:
    $ 309.22万
  • 项目类别:

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