Predicting neonatal health outcomes from placental and fetal brain extracellular vesicles in pregnant opioid users

项目摘要 我们提交这项提案是对RFA-HD-23-032(Hear倡议：阿片类药物暴露和影响 胎盘功能、脑发育和神经发育结果)。 新生儿阿片类药物戒断综合征(NOWS)的新生儿发生率在过去显著增加 十年。NOW具有长期的健康后果，包括生长不良、癫痫发作和改变 神经发育和认知功能。然而，并不是所有在怀孕期间接触阿片类药物的新生儿 发展NOW或需要治疗。无法预测哪些婴儿会经历NOWS并需要 药物疗法。母亲阿片类药物剂量不是NOWS的预测因子，尽管遗传学和共同暴露于 其他药物已经与NOWS的严重程度相关，还没有确定预测NOWS风险的因素。 此外，一些婴儿发生NOWS而另一些婴儿不发生NOWS的机制尚不清楚。 可获得的阿片类药物使用引起的胎盘和胎儿大脑变化的生物标志物将高度 对决定哪些婴儿需要阿片类药物治疗NOWS并制定个性化风险很有价值 对接触阿片类药物的婴儿进行评估。它们还可以揭示导致 怀孕期间接触阿片类药物的最严重影响。 来源于胎盘(PEV)或胎脑和中枢神经系统(FNEV)的细胞外小泡(EVS) 可以穿过胎儿/胎盘屏障，并可以从母亲的血液中分离出来。他们代表着一种强大的 易于获取的工具，可深入了解胎盘健康和胎儿神经发育及损伤。这个项目将 健康妊娠和合并使用阿片类药物妊娠的PEV和FNEV的特征 精神障碍，根据NOWS药物治疗的需要进行分层。对于PEV，我们将专注于胎盘压力的小组 和5-羟色胺处理标记，而对于FNEV，我们将专注于报告在大脑中发生变化的标记 在怀孕期间接触阿片类药物后。我们的研究将导致对NOWS风险进行产前和 将为受阿片类药物使用影响的分子途径带来新的见解。

Project Summary We are submitting this proposal in response to RFA-HD-23-032 (HEAL initiative: Opioid Exposure and Effects on Placenta Function, Brain Development, and Neurodevelopmental Outcomes). The rate of newborns with neonatal opioid withdrawal syndrome (NOWS) increased dramatically over the past decade. NOWS has long-term health consequences including poor growth, seizures, and altered neurodevelopmental and cognitive function. However, not all neonates exposed to opioids during gestation develop NOWS or require treatment. It is impossible to predict which infants will experience NOWS and require pharmacotherapy. Maternal opioid dose is not a predictor for NOWS, and though genetics and co-exposure to other drugs have been associated with NOWS severity, no factors have been identified that predict NOWS risk. Further, the mechanisms by which some infants develop NOWS while others do not are not understood. Accessible biomarkers of changes induced by opioid use for the placental and fetal brain would be highly valuable for deciding which infants will need opioid therapy for NOWS and making personalized risk assessments for opioid exposed infants. They could also shed light on the biological pathways that lead to the worst effects of opioid exposure during gestation. Extracellular vesicles (EVs) derived from the Placenta (PEV) or Fetal brain and central Nervous system (FNEV) can cross the fetal/placental barrier and can be isolated from maternal blood. They represent a powerful accessible tool to provide insight on placental health and fetal neurodevelopment and damage. This project will characterize PEVs and FNEVs profiles in healthy pregnancies and from pregnancies complicated by opioid use disorder, stratified by need for NOWS pharmacotherapy. For PEVs, we will focus on a panel of placental stress and serotonin processing markers, and for FNEVs we will focus on markers reported to be altered in the brains following opioid exposure during gestation. Our studies will lead to assays that define NOWS risk pre-birth and will bring new insights into the molecular pathways impacted by opioid use.