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

基本信息

批准号：
10552037
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
项目类别：
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/10552037
关键词：
Adenine Adult Affect Affinity Chromatography Alleles Animal Model Anti-Inflammatory Agents Area Behavior Behavioral Biological Assay Biological Response Modifiers Brain region Breeding 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 Inflammatory Innate Immune Response Innate Immune System 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 complement system cytokine experience experimental study gastrointestinal gene discovery genetic risk factor genomic variation glial activation 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

项目摘要

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.

项目概要孕妇使用阿片类药物是美国日益严重的公共卫生问题在子宫内接触阿片类药物的婴儿出现新生儿阿片类药物的风险很高。戒断综合症（NOWS），一种身体戒断症状的组合，包括高声哭泣、失眠、烦躁、肠胃不适，最糟糕的是多种临床因素加剧了这种综合征的复杂性。例如母亲阿片类药物暴露的持续时间、母亲多重用药、环境和子宫内阿片类药物暴露和NOWS 的复杂性使其非常困难。研究最终可以为早期诊断提供信息的潜在分子机制因此，我们开发了急需的3-小鼠模型。根据初步证据，我们服用了妊娠期阿片类药物的暴露和戒断。小胶质细胞激活和免疫介质导致了NOWS 的严重程度 -阿片受体中的一个常见 SNP 可调节这些作用。原型阿片类药物，我们将利用我们的模型来测试这些假设。描述先天免疫系统在 NOWS 中的作用并确定调节是否有效神经炎症的药物治疗具有治疗潜力炎症药物异丁司特其次，最近的临床发现表明基因组。编码 -阿片受体 (Oprm1 A118G) 的基因的变异可能会影响现在严重性，我们将使用包含等效 Oprm1 A118G 的鼠标系列 SNP 确定 Oprm1 遗传学对小胶质细胞激活和免疫的影响使用我们的三个月期阿片类药物暴露和戒断模型，我们将使用 TRAP-Seq，一种用于检索核糖体复合物中 mRNA 的新技术在我们的例子中，在表达 m-阿片受体的细胞中积极地被翻译，以询问阿片类药物暴露和戒断后转录组的变化很可能是这个项目。对该领域产生持续而强大的影响，因为我们将解决围产期接触阿片类药物导致 NOWS 的机制，以及如何遗传和免疫反应有所贡献。