Neonatal Opioid Exposure and Withdrawal: Molecular and Behavioral Consequences

新生儿阿片类药物暴露和戒断：分子和行为后果

• 批准号: 10347354
• 负责人: Julie A Blendy
• 金额: $ 69.65万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10347354
• 关键词: Address; Adenine; Adult; Affect; Affinity Chromatography; Alleles; Animal Model; Anti-Inflammatory Agents; Area; Behavior; Behavioral; Biological Assay; Biological Response Modifiers; Brain region; Canis familiaris; Cells; Clinical; Complex; Crying; Data; Development; Diarrhea; Distress; Early Diagnosis; Early treatment; Enterobacteria phage P1 Cre recombinase; Environment; Exhibits; Exposure to; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Genotype; Guanine; Heroin; Hospitals; Hour; Human; Immune; Immune response; Immunosuppression; Infant; Innate Immune Response; Innate Immune System; Lead; Length of Stay; Life; Link; Lymphokines; Measures; Mediating; Messenger RNA; Methadone; Microglia; Modeling; Molecular; Morphine; Mus; Natural Immunity; Neonatal; Neonatal Abstinence Syndrome; Neuroimmune system; Newborn Infant; Nucleus Accumbens; Opiate Addiction; Opioid; Opioid Receptor; Pain; Pathway interactions; Perinatal Exposure; Peripheral; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Polypharmacy; Pregnant Women; Presynaptic Terminals; Public Health; Receptor Cell; Receptor Gene; Regulation; Ribosomes; Risk; Role; Seizures; Severities; Single Nucleotide Polymorphism; Sleeplessness; Syndrome; Testing; Therapeutic; Time; Tooth structure; Translating; Tremor; United States; Weight Gain; Wild Type Mouse; Withdrawal; Withdrawal Symptom; base; complement system; cytokine; experience; experimental study; gastrointestinal; gene discovery; genetic risk factor; genomic variation; high risk; in utero; insight; interest; midbrain central gray substance; molecular marker; mouse model; mu opioid receptors; neonate; neuroinflammation; neuronal cell body; new technology; novel; novel therapeutics; opioid epidemic; opioid exposure; opioid use; opioid withdrawal; pup; response; transcriptome

Project Summary Opioid use among pregnant women is a growing public health concern in the United States. Infants exposed to opioids in utero are at high risk of exhibiting Neonatal Opioid Withdrawal Syndrome (NOWS), a combination of physical withdrawal symptoms including high pitched crying, sleeplessness, irritability, gastrointestinal distress, and in the worst cases, seizures. The complexity of this syndrome is amplified by a variety of clinical factors such as duration of maternal opioid exposure, maternal polypharmacy, environment, and genetics. The complexity of in utero opioid exposure and NOWS make it very difficult to investigate underlying molecular mechanisms that could ultimately inform early diagnosis and treatment. Therefore, we have developed a much needed mouse model of 3- trimester opioid exposure and withdrawal. Based on preliminary evidence, we hypothesize that microglia activation and immune mediators contribute to the severity of NOWS and a common SNP in the -opioid receptor modulates these effects. Using morphine as a prototypical opioid, we will exploit our model to test these hypotheses. First we will fully characterize the role of the innate immune system in NOWS and determine if regulation of neuroinflammation has therapeutic potential by pharmacological treatment with the anti- inflammatory drug, ibudilast. Second, as recent clinical findings suggest that genomic variation in the gene that encodes the -opioid receptor (Oprm1 A118G) may influence NOWS severity, we will use our mouse line that contains the equivalent Oprm1 A118G SNP to determine the impact of Oprm1 genetics on microglia activation and immune mediators. Using our model of 3-trimester opioid exposure and withdrawal we will use TRAP-Seq, a new technology for retrieving mRNAs within the ribosomal complex that are actively being translated, in our case in cells expressing m-opioid receptors, to interrogate the changing transcriptome following opioid exposure and withdrawal. This project is likely to have a sustained and powerful impact on the field because we will address mechanisms through which perinatal exposure to opiates results in NOWS, and how genetics and immune response contribute.

项目摘要 孕妇中使用阿片类药物是曼联越来越多的公共卫生问题 国家。在子宫内暴露于阿片类药物的婴儿面临新生儿阿片类药物的高风险 戒断综合征（现在），包括身体戒断症状的结合 高高的哭泣，失眠，烦躁，胃肠道痛苦，在最糟糕的情况下 案件，癫痫发作。该综合征的复杂性通过多种临床因素扩大 例如母体阿片类药物的持续时间，母体多药，环境和 遗传学。子宫阿片类药物暴露的复杂性，现在使很难 调查最终可能为早期诊断提供信息的潜在分子机制 和治疗。因此，我们开发了急需的3-的小鼠模型 孕期阿片类药物暴露和戒断。根据初步证据，我们假设 小胶质细胞的激活和免疫介质有助于现状的严重程度 阿片受体中的常见SNP可调节这些作用。使用吗啡作为 原型阿片类药物，我们将利用我们的模型来检验这些假设。首先，我们将完全 表征先天免疫系统在Nows中的作用，并确定是否调节 神经炎症具有通过药物治疗的治疗潜力 炎症药，ibudilast。其次，正如最近的临床发现表明基因组 编码阿片受体（OPRM1 A118G）的基因变异可能会影响 现在的严重性，我们将使用包含等效OPRM1 A118G的鼠标线 SNP确定OPRM1遗传学对小胶质细胞激活和免疫的影响 调解人。使用我们的3孕期阿片类药物暴露和戒断的模型，我们将使用 Trap-Seq，一种用于在核糖体综合体中检索mRNA的新技术 在我们的情况下，在表达M-阿片类受体的细胞中积极翻译以询问 阿片类药物暴露和退出后的转录组变化。这个项目可能是 对该领域产生持续和强大的影响，因为我们将解决 围产期暴露以优化现实结果的机制，以及如何 遗传学和免疫响应贡献。