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Strategies to define and mitigate the placental and fetal alterations caused by maternal oxycodone exposure

确定和减轻母体羟考酮暴露引起的胎盘和胎儿改变的策略

基本信息

批准号：
10750458
负责人：
Lynda Katherine Harris
金额：
$ 265.5万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
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：
2023-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10750458
关键词：
Address Adverse effects Affect Affinity Analgesics Anti-Inflammatory Agents Antioxidants Architecture Behavior Behavioral Behavioral Assay Behavioral Mechanisms Binding Biological Markers Birth Brain Cells Child Childhood Clinical Cognition Cognitive deficits Development Developmental Process Diagnosis Embryo Enzyme-Linked Immunosorbent Assay Exposure to Fentanyl Fetal Development Fetal Growth Fetal Growth Retardation Fetal Monitoring Fetus Functional disorder Gene Expression Goals Growth Factor Guidelines Heroin High Pressure Liquid Chromatography Histologic Hormonal Hormones Human Image Immune Impairment Individual Inflammation Inflammatory Intervention Intervention Studies Link Measures Melatonin Methadone Mission Modeling Molecular Profiling Monitor Morphine Motor Skills Mus National Institute of Child Health and Human Development National Institute of Drug Abuse National Institute of Neurological Disorders and Stroke Neonatal Abstinence Syndrome Neonatal Brain Injury Neurologic Neurotransmitter Receptor Neurotransmitters Newborn Infant Opioid Opioid Receptor Organ Outcome Oxidative Stress Oxycodone Pain Pain Threshold Pathology Patient Self-Report Placenta Placentation Plasma Play Predisposition Pregnancy Production Property Rattus Reaction Reflex action Research Personnel Research Support Reverse Transcriptase Polymerase Chain Reaction Risk Rodent Model Second Pregnancy Trimester Stress Structure Surface Synapses Systems Biology Technology Testing Therapeutic Third Pregnancy Trimester Time Tissue imaging Tissues Treatment Efficacy Ultrasonics Uterus Work addiction anxiety-like behavior behavioral outcome behavioral study biomarker identification blood-brain barrier crossing clinically relevant fetal improved in utero infancy kappa opioid receptors maladaptive behavior maternal opioid use melatonin supplementation motor behavior multimodality neurodevelopment neuroprotection novel offspring opioid abuse opioid exposure opioid use disorder opioid use in pregnancy postnatal preclinical study pregnant prenatal prenatal exposure prescription opioid prescription opioid abuse prescription opioid misuse protein expression pup response sex single-cell RNA sequencing trophoblast vocalization

项目摘要

PROJECT SUMMARY In the US alone, 1.5% of pregnant individuals self-report misuse of prescription opioids, and almost 80 newborns a day are diagnosed with neonatal opioid withdrawal syndrome. In utero opioid exposure causes fetal growth restriction, alters fetal brain development and causes deficits in cognition, motor skills and behavior in affected children. However, the mechanisms by which opioids dysregulate neurodevelopment are currently unknown. The placenta is a critical regulator of fetal development, and emerging evidence suggests that opioids also impair placental development. The overarching aim of this project is to define the developmental processes in the placenta and fetal brain that are dysregulated by opioid exposure, and develop strategies to mitigate the resulting pathology. Oxycodone (oxy) is one of the most commonly abused opioids and crosses the placenta to a greater extent than morphine, heroin fentanyl and methadone. This proposal will test the hypotheses that in rats, in utero oxy exposure leads to alterations in maternal circulating factors, placental structure and function, and fetal neurodevelopment and behavior, and that these changes can be mitigated using melatonin supplementation to correct the abnormal pathophysiology. Placental and fetal brain ultrastructure and gene expression will be comprehensively assessed at mid pregnancy (embryonic (E) day 12.5, when the placenta is fully formed), and just before birth (E19.5), using state of the art technologies including single cell RNA sequencing and X-CLARITY whole organ imaging. Evidence of inflammation, oxidative stress and dysregulated hormone production in maternal plasma, fetal and placental tissues will be also be evaluated. In parallel, changes in the expression of growth factors, inflammatory molecules, immune cells and neurotransmitters in the brains of 4- and 14-day old rat pups exposed to oxy in utero will also be measured, which will be correlated with behavioral studies undertaken at the same time points. These observations will provide the first integrated analysis of the key structural and functional abnormalities, hormonal, and neurodevelopmental changes occurring at the maternofetal interface in response to oxy exposure, and link them to alterations in offspring behavior. The ability of melatonin, a naturally occurring, anti-inflammatory, antioxidant and neuroprotective hormone, to reduce the degree of placental and/or fetal pathophysiology observed, will also be assessed. Successful completion of this proposal, using a translationally-relevant rodent model, will provide a robust framework on which to identify key developmental processes that are susceptible to dysregulation by oxy. These studies, which are not possible in humans, have the potential to inform the first biomarker, fetal monitoring and interventional studies in human pregnancy, providing improved clinical guidelines and treatments for individuals affected by opioid use disorder, thereby aligning with the missions of the NICHD, NIDA and NINDS.

项目总结