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:9911467
- 负责人:
- 金额:$ 71.08万
- 依托单位:
- 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:
- 关键词:AddressAdenineAdultAffectAffinity ChromatographyAllelesAnimal ModelAnti-Inflammatory AgentsAreaBehaviorBehavioralBiological AssayBiological Response ModifiersBrain regionCanis familiarisCellsClinicalComplexCryingDataDevelopmentDiarrheaDistressEarly DiagnosisEarly treatmentEnterobacteria phage P1 Cre recombinaseEnvironmentExhibitsExposure toGenesGeneticGenetic Predisposition to DiseaseGenomicsGenotypeGuanineHeroinHospitalsHourHumanImmuneImmune responseImmunosuppressionInfantInnate Immune ResponseInnate Immune SystemLeadLength of StayLifeLinkLymphokinesMeasuresMediatingMessenger RNAMethadoneMicrogliaModelingMolecularMorphineMusNatural ImmunityNeonatalNeonatal Abstinence SyndromeNeuroimmune systemNewborn InfantNucleus AccumbensOpiate AddictionOpioidOpioid ReceptorPainPathway interactionsPerinatal ExposurePeripheralPharmaceutical PreparationsPharmacological TreatmentPhenotypePolypharmacyPregnant WomenPresynaptic TerminalsPublic HealthReceptor CellReceptor GeneRegulationRibosomesRiskRoleSeizuresSeveritiesSingle Nucleotide PolymorphismSleeplessnessSyndromeTestingTherapeuticTimeTooth structureTranslatingTremorUnited StatesWeight GainWild Type MouseWithdrawalWithdrawal Symptombasecomplement systemcytokineexperienceexperimental studygastrointestinalgene discoverygenetic risk factorgenomic variationhigh riskin uteroinsightinterestmidbrain central gray substancemolecular markermouse modelmu opioid receptorsneonateneuroinflammationneuronal cell bodynew technologynovelnovel therapeuticsopioid epidemicopioid exposureopioid useopioid withdrawalpupresponsetranscriptome
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.
项目摘要
在美国,孕妇使用阿片类药物是一个日益严重的公共卫生问题。
States.在子宫内暴露于阿片类药物的婴儿患新生儿阿片类药物的风险很高
戒断综合征(NOWS),一种身体戒断症状的组合,包括
高音调的哭泣,失眠,易怒,胃肠道不适,最严重的是
病例癫痫这种综合征的复杂性被各种临床因素放大
如母体阿片类药物暴露持续时间、母体多种用药、环境,
遗传学子宫内阿片类药物暴露和NOWS的复杂性使得很难
研究可能最终为早期诊断提供信息的潜在分子机制
和治疗。因此,我们开发了一种急需的3-
妊娠期阿片类药物暴露和戒断。基于初步证据,我们假设
小胶质细胞激活和免疫介质有助于NOWS的严重性,
β-阿片受体中的一种常见SNP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测试这些假设。首先,我们将全面
描述先天免疫系统在NOWS中的作用,并确定是否调节
的神经炎症具有治疗潜力的药物治疗与抗-
消炎药异丁司特其次,最近的临床研究结果表明,
编码β-阿片受体(Oprm 1 A118 G)的基因的变异可能会影响
NOWS严重性,我们将使用包含等效Oprm 1 A118 G的鼠标线
SNP以确定Oprm 1遗传学对小胶质细胞活化和免疫的影响
调解员使用我们的3个月阿片类药物暴露和戒断模型,我们将使用
TRAP-Seq是一种新技术,用于检索核糖体复合物中的mRNA,
在我们的情况下,在表达m-阿片受体的细胞中,
阿片类药物暴露和戒断后转录组的变化。这个项目很可能
对该领域产生持续和强大的影响,因为我们将解决
围产期暴露于阿片类药物导致NOWS的机制,以及如何
遗传学和免疫反应的影响。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Julie A Blendy其他文献
Julie A Blendy的其他文献
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{{ truncateString('Julie A Blendy', 18)}}的其他基金
Low-input profiling of brain-region and cell-type specific epigenomic dynamics to understand gene-environment interactions in opioid addiction
对大脑区域和细胞类型特异性表观基因组动力学进行低输入分析,以了解阿片类药物成瘾中的基因与环境的相互作用
- 批准号:
10605801 - 财政年份:2023
- 资助金额:
$ 71.08万 - 项目类别:
Mapping opioid-dependence state transitions across structural, functional, and transcriptomic topologies
绘制结构、功能和转录组拓扑中阿片类药物依赖性状态转变的图谱
- 批准号:
10293782 - 财政年份:2021
- 资助金额:
$ 71.08万 - 项目类别:
Mapping opioid-dependence state transitions across structural, functional, and transcriptomic topologies
绘制结构、功能和转录组拓扑中阿片类药物依赖性状态转变的图谱
- 批准号:
10493185 - 财政年份:2021
- 资助金额:
$ 71.08万 - 项目类别:
Mapping opioid-dependence state transitions across structural, functional, and transcriptomic topologies
绘制结构、功能和转录组拓扑中阿片类药物依赖性状态转变的图谱
- 批准号:
10622531 - 财政年份:2021
- 资助金额:
$ 71.08万 - 项目类别:
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 - 财政年份:2020
- 资助金额:
$ 71.08万 - 项目类别:
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:
10552037 - 财政年份:2020
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AMP-activated protein kinase (AMPK) and nicotine dependence
AMP 激活蛋白激酶 (AMPK) 和尼古丁依赖性
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9441755 - 财政年份:2016
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$ 71.08万 - 项目类别:
T32 Translational Addiction Research Fellowship Program
T32 转化成瘾研究奖学金计划
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10159223 - 财政年份:2010
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$ 71.08万 - 项目类别:
T32 Translational Addiction Research Fellowship Program
T32 转化成瘾研究奖学金计划
- 批准号:
10628649 - 财政年份:2010
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$ 71.08万 - 项目类别:
T32 Translational Addiction Research Fellowship Program
T32 转化成瘾研究奖学金计划
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10400087 - 财政年份:2010
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$ 71.08万 - 项目类别:
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