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

项目摘要 我们提交本提案是为了响应RFA-HD-23 - 032（HEAL倡议：阿片类药物暴露和影响 胎盘功能，大脑发育和神经发育结果）。 新生儿阿片类戒断综合征（NOWS）的发生率在过去急剧增加 十年NOWS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，并非所有在妊娠期间暴露于阿片类药物的新生儿 出现NOWS或需要治疗。不可能预测哪些婴儿会经历NOWS， 药物治疗.母体阿片剂量不是NOWS的预测因子，尽管遗传学和共同暴露于 其他药物与NOWS严重程度相关，但尚未确定预测NOWS风险的因素。 此外，一些婴儿发展NOWS而另一些婴儿不发展NOWS的机制尚不清楚。 阿片类药物使用诱导的胎盘和胎儿大脑变化的生物标志物可能是高度敏感的。 对于决定哪些婴儿需要阿片类药物治疗NOWS和制定个性化风险评估有价值 评估阿片类药物暴露的婴儿。他们还可以揭示导致癌症的生物学途径， 妊娠期间阿片类药物暴露的最坏影响。 来源于胎盘（PEV）或胎脑和中枢神经系统（FNEV）的细胞外囊泡（EV） 可以穿过胎儿/胎盘屏障并可以从母体血液中分离。他们代表了一个强大的 这是一个易于使用的工具，可以提供有关胎盘健康和胎儿神经发育和损伤的见解。该项目将 描述健康妊娠和阿片类药物使用并发妊娠的PEV和FNEV特征 疾病，根据对NOWS药物治疗的需求分层。对于PEV，我们将重点关注胎盘应激 和5-羟色胺加工标记物，对于FNEV，我们将重点关注据报道在大脑中改变的标记物 在妊娠期间暴露于阿片类药物。我们的研究将导致确定出生前NOWS风险的测定， 将为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.