Multimodal Fetal and Placental Imaging and Biomarkers of Clinical Outcomes in Opioid Use Disorder

阿片类药物使用障碍临床结果的多模态胎儿和胎盘成像和生物标志物

基本信息

批准号：
10750306
负责人：
Rupa Radhakrishnan
金额：
$ 314.53万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750306
关键词：
2 year old Address Affect American Asphyxia Neonatorum Biological Markers Blood Brain Brain region Buprenorphine CCL17 gene COVID-19 pandemic Child Childhood Clinical Cognitive DNA Data Development Dimensions Economic Burden Epigenetic Process Fetal Development Fetal health Fetus Functional Magnetic Resonance Imaging Functional disorder Genes Genetic Genetic Variation Genomics Goals Growth Health Image Impairment Infant Infant Development Interleukin-1 beta Interleukin-2 Knowledge Length of Stay Link Magnetic Resonance Imaging Mental Depression Metabolic Pathway Metabolism Methadone Methylation MicroRNAs Mothers Multimodal Imaging Neonatal Abstinence Syndrome Opioid Outcome Pharmacogenetics Pilot Projects Placenta Pregnancy Pregnancy Proteins Pregnant Women Premature Birth Proteome Proteomics Psychological Factors Public Health Relapse Reporting Research Research Personnel Rest Risk Safety Second Pregnancy Trimester Severities Site Smoking Structure Third Pregnancy Trimester Tissues Toddler Variant Vascular Endothelial Growth Factor D Work adverse outcome adverse pregnancy outcome behavioral outcome blood oxygen level dependent brain magnetic resonance imaging circulating biomarkers comparison control epigenetic marker fetal fetal opioid exposure high risk imaging biomarker improved individualized prevention infant outcome innovation magnetic resonance imaging biomarker maternal comorbidity maternal opioid use maternal outcome maternal risk medication for opioid use disorder morphometry multidisciplinary multimodality neurobehavioral neurodevelopment neuroimaging non-opioid analgesic novel opioid epidemic opioid use disorder opioid use in pregnancy personalized predictions placental morphology polysubstance use public health relevance risk mitigation serial imaging socioeconomics substance use tissue biomarkers tool uptake

项目摘要

PROJECT SUMMARY Maternal Opioid Use Disorder (OUD) and Neonatal Opioid Withdrawal Syndrome (NOWS) have dramatically increased, with an American child born suffering from NOWS every 15 minutes. The exponentially increasing prenatal opioid exposure (POE) and ongoing opioid epidemic are further worsened by the COVID-19 pandemic. Mothers with OUD are at risk of adverse pregnancy outcomes, and infants with POE are at risk for NOWS and poor long-term neurobehavioral outcomes; there are currently no objective tools for early prediction or mitigation of these risks. Our previous studies have shown MR imaging alterations in brain structural and resting state functional network connectivity in infants with POE compared to non-opioid exposed healthy infants. Specifically, we showed that, in infants with POE, thalamo-frontal functional connectivity correlated with severity of NOWS and was modulated by maternal comorbidities. Infant brain structural and functional development is dependent on placenta-fetal health. We identified smaller cerebellar dimensions in fetuses with prenatal opioid exposure and showed alterations in placental size in pregnant women on OUD who had concomitant smoking or polysubstance use. We also showed that opioid related poor childhood clinical outcomes are related to opioid pharmacogenetic variations, and that placental epigenetics is correlated with neonatal opioid withdrawal syndrome in POE. Our pilot data show that toddlers treated for NOWS score poorly on the cognitive domain of the Bayley Scales of Infant Development-III. Based on our pilot work, we hypothesize that opioids affect longitudinal fetal brain development resulting in adverse long-term childhood neurobehavioral outcomes and that these fetal brain effects are moderated by placental dysfunction and maternal comorbidities. There is a critical and urgent unmet need for proactive identification of novel comprehensive multimodal markers of placental and fetal brain growth and function to predict adverse maternal and infant outcomes in maternal OUD. Our long-term goal is to improve safety and efficacy of OUD treatment during pregnancy, and significantly reduce the risks of NOWS, poor childhood neurodevelopment and maternal relapse. The Specific Aims are to 1) determine the effects of opioids on the developing fetal brain through longitudinal structural and functional fetal brain MRI, 2) assess the impact of opioids on placental morphology and function through placental imaging, epigenetics, proteomics and opioid pharmacogenetics, and 3) correlate impaired fetal brain development and placental function with NOWS and infant neurodevelopmental outcomes. The expected outcomes are to identify 1) critical longitudinal imaging markers of placental dysfunction and altered fetal brain development in maternal OUD; 2) novel opioid pharmacogenetic, epigenetic and proteomic biomarkers of placental dysfunction in OUD and NOWS, and 3) comprehensive and advanced placental-fetal imaging, and circulating proteomic and placental epigenetic biomarkers of severity of NOWS and poor infant neurodevelopmental outcome.

项目概要孕产妇阿片类药物使用障碍 (OUD) 和新生儿阿片类药物戒断综合征 (NOWS) 增加，每 15 分钟就有一名美国婴儿出生时患有NOWS。呈指数级增长 COVID-19 大流行进一步加剧了产前阿片类药物暴露 (POE) 和持续的阿片类药物流行。患有 OUD 的母亲面临不良妊娠结局的风险，患有 POE 的婴儿面临 NOWS 和长期神经行为结果不佳；目前没有客观的工具来进行早期预测或缓解这些风险。我们之前的研究表明，磁共振成像会改变大脑结构和静息状态与未暴露于阿片类药物的健康婴儿相比，POE 婴儿的功能网络连接性。具体来说，我们发现，在患有 POE 的婴儿中，丘脑-额叶功能连接与 NOWS 的严重程度相关并受到母亲合并症的调节。婴儿大脑的结构和功能发育取决于关于胎盘胎儿健康。我们发现产前阿片类药物暴露的胎儿小脑尺寸较小并显示服用 OUD 且同时吸烟或吸烟的孕妇胎盘大小发生变化多物质的使用。我们还表明，阿片类药物相关的不良儿童临床结果与阿片类药物相关药物遗传学变异，胎盘表观遗传学与新生儿阿片类药物戒断相关 POE综合症。我们的试点数据显示，接受 NOWS 治疗的幼儿在认知领域得分很低贝利婴儿发育量表-III。根据我们的试点工作，我们假设阿片类药物会影响胎儿大脑的纵向发育导致不良的长期儿童神经行为结果这些胎儿大脑的影响会受到胎盘功能障碍和母亲合并症的影响。有一个关键的以及主动识别胎盘和胎盘的新型综合多模态标记物的迫切未满足的需求胎儿大脑生长和功能可预测母体 OUD 中母婴不良结局。我们的长期目标是提高妊娠期间 OUD 治疗的安全性和有效性，并显着降低妊娠期 OUD 治疗的风险现在，儿童神经发育不良和产妇复发。具体目标是 1) 确定通过纵向结构和功能性胎儿大脑 MRI 观察阿片类药物对胎儿大脑发育的影响，2) 通过胎盘成像、表观遗传学、蛋白质组学和阿片类药物遗传学，3) 将受损的胎儿大脑发育和胎盘相关联与NOWS 和婴儿神经发育结果的功能。预期结果是确定 1) 关键母体 OUD 中胎盘功能障碍和胎儿大脑发育改变的纵向成像标记； 2） OUD 和胎盘功能障碍的新型阿片类药物遗传学、表观遗传学和蛋白质组生物标志物 NOWS，3) 全面和先进的胎盘胎儿成像，以及循环蛋白质组和胎盘 NOWS 严重程度和婴儿神经发育结果不良的表观遗传生物标志物。