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

通过妊娠阿片类药物使用者的胎盘和胎儿脑细胞外囊泡预测新生儿健康结果

• 批准号: 10747661
• 负责人: Daniel T Chiu
• 金额: $ 226.78万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747661
• 关键词: Address; Affect; Alkaline Phosphatase; Biological; Biological Assay; Biological Markers; Birth; Blood; Brain; Central Nervous System; Circulation; Clinical; Communication; Complex; Development; Dose; Dyes; Enzyme-Linked Immunosorbent Assay; Exposure to; Fetal health; Fetus; Flow Cytometry; Fluorescence-Activated Cell Sorting; Genetic; Growth; HLA G antigen; Health; Helping to End Addiction Long-term; Individual; Infant; Liquid substance; Mediator; Molecular; Neonatal Abstinence Syndrome; Newborn Infant; Opioid; Opioid Receptor; Organ; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Placenta; Plasma; Population; Population Heterogeneity; Pregnancy; Pregnancy Complications; Proteins; Public Health; RNA; RNA marker; Regulation; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Assessment; Second Pregnancy Trimester; Seizures; Selective Serotonin Reuptake Inhibitor; Serotonin; Severities; Sorting; Source; Stress; Synaptophysin; Techniques; Technology; Third Pregnancy Trimester; United States; Western Blotting; Woman; biological heterogeneity; candidate identification; candidate marker; cognitive function; contactin; experience; extracellular vesicles; fetal; fluorophore; healthy pregnancy; in utero; insight; interest; maternal opioid use; microRNA biomarkers; nanoparticle; neonatal health; neonate; neurodevelopment; new technology; opioid epidemic; opioid exposure; opioid therapy; opioid use; opioid use disorder; opioid user; pregnant; protein biomarkers; response; screening; serotonin receptor; syncytin; tool

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.

项目概要 我们提交此提案是为了回应 RFA-HD-23-032（HEAL 倡议：阿片类药物暴露和影响 关于胎盘功能、大脑发育和神经发育结果）。 新生儿阿片戒断综合征（NOWS）的发生率在过去急剧增加 十年。 NOWS 会对健康产生长期影响，包括生长不良、癫痫发作和改变 神经发育和认知功能。然而，并非所有新生儿在妊娠期间都接触阿片类药物 出现NOWS 或需要治疗。无法预测哪些婴儿会经历NOWS 并需要 药物治疗。母亲阿片类药物剂量并不是 NOWS 的预测因素，尽管遗传和共同暴露 其他药物已与 NOWS 严重程度相关，但尚未确定可预测 NOWS 风险的因素。 此外，一些婴儿发展为NOWS 而另一些婴儿则不发展的机制尚不清楚。 使用阿片类药物引起的胎盘和胎儿大脑变化的可获取生物标志物将非常重要 对于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 对阿片类药物暴露婴儿的评估。他们还可以揭示导致这一现象的生物学途径。 妊娠期间阿片类药物暴露的最严重影响。 源自胎盘 (PEV) 或胎儿大脑和中枢神经系统 (FNEV) 的细胞外囊泡 (EV) 可以穿过胎儿/胎盘屏障，并可以从母血中分离出来。他们代表着强大的力量 易于使用的工具，可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 药物治疗的需要进行分层。对于 PEV，我们将重点关注一组胎盘应激 和血清素处理标记物，对于 FNEV，我们将重点关注据报告在大脑中发生改变的标记物 妊娠期间接触阿片类药物后。我们的研究将导致确定产前和 将为阿片类药物使用影响的分子途径带来新的见解。