POPI: Placenta, Opioids and Perinatal Implications

总结 近年来，母体阿片类药物的使用急剧增加， 后代的健康。来自动物模型和临床研究的数据表明，产前阿片类药物暴露是 与早产、胎儿生长受限、低出生体重、新生儿阿片类药物戒断显著相关 综合征，较小的大脑尺寸和受损的神经行为结果。然而，机械 对这些不良后果的基础仍然知之甚少。现有的公布数据和我们的 初步研究强烈表明，母体阿片类药物使用障碍（OUD）扰乱胎盘-大脑 轴线一个潜在的机制是OUD破坏胎盘发育和功能，损害营养和 母亲和胎儿之间的气体交换。另一个机制是阿片类药物在胎盘组织中积累， 从而直接破坏正常的胎儿发育。然而，分子基础和贡献 对每一种途径的了解仍然很少。因此，本申请将检验中心假设， 母体OUD驱动的炎症和胎盘景观的失调与不利的 神经认知的结果。这种应用的新奇在于系统生物学方法 在母胎界面整合表型、功能和基因组读数的脐带血 在分娩时，新生儿血液与神经行为和运动技能评估在整个第一年的 生活完成拟议的实验将导致对胎盘失调的新见解- 脑轴引起的母亲OUD，并将铺平道路，建立一个全面的结构，并告知 在暴露于阿片类药物的妊娠期间制定早期干预措施。

SUMMARY Maternal opioid use, which dramatically increased in recent years, exerts severe adverse consequences for the offspring’s health. Data from animal models and clinical studies demonstrated that prenatal opioid exposure is significantly associated with preterm birth, fetal growth restriction, low birth weights, neonatal opioid withdrawal syndrome, smaller brain sizes, and impaired neurobehavioral outcomes. However, the mechanistic underpinnings of these adverse outcomes remain poorly understood. Available published data and our preliminary studies strongly suggest that maternal opioid use disorder (OUD) perturbs the placenta-brain axis. One potential mechanism is that OUD disrupts placental development and function, impairing nutrient and gas exchange between mother and fetus. Another mechanism is that opioids accumulate in placental tissues, thereby directly disrupting normal fetal development. However, the molecular underpinnings and the contribution of each pathway remain poorly understood. Therefore, this application will test the central hypothesis that maternal OUD driven inflammation and dysregulation of the placental landscape are linked to adverse neurocognitive outcomes in the offspring. The novelty of this application lies in the systems biology approach that integrates phenotypic, functional, and genomic readouts at the maternal-fetal interface, umbilical cord blood at delivery, and neonatal blood with neurobehavioral and motor skill assessments throughout the first year of life. Completion of the proposed experiments will result in novel insights into the dysregulations of the placenta- brain axis elicited by maternal OUD and will pave the way to building a comprehensive construct and inform the development of early interventions during opioid-exposed pregnancies.