Impact of maternal marijuana use on epigenetic regulation of offspring neurodevelopment
母亲吸食大麻对后代神经发育的表观遗传调控的影响
基本信息
- 批准号:10705157
- 负责人:
- 金额:$ 52.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-15 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAttention deficit hyperactivity disorderBehaviorBehavioralBindingBrainCannabinoidsChronicCognitionCorpus striatum structureDataDevelopmentDiseaseDrug AddictionEarly InterventionEnvironmental ExposureEpigenetic ProcessFetal DevelopmentFetal GrowthGene Expression RegulationGoalsHealthHigh PrevalenceInfantInflammatoryLactationLifeLinkMapsMarijuanaMediatingModelingModificationMolecularMorbidity - disease rateOutcomePlacentaPlayPregnancyPsychotropic DrugsRegulationRiskRoleSecondary toSignal TransductionTHC exposureTetrahydrocannabinolTissue SampleTissuesWomanaddictionautism spectrum disorderbehavioral studycannabinoid receptorcognitive disabilitydrug of abuseearly childhoodearly screeningepigenetic regulationfetalfetal marijuana exposurefetus nutritionhistone modificationillicit drug useimaging capabilitiesimaging studyin uteroin vivoin vivo imaginginnovationinsightmarijuana usematernal marijuana useneurodevelopmentnonhuman primatenoveloffspringpostnatalpregnantprenatalresponsereward processingtranscriptomicstranslational impacttransmission processtrying to conceive
项目摘要
PROJECT SUMMARY
Marijuana is now the most commonly used illicit drug in pregnancy. The main psychoactive compound of
marijuana, delta-9-tetrahydrocannabinol (THC), can access and bind to cannabinoid receptors in the placenta
and fetal brain. Preliminary data suggest that prenatal cannabinoid exposure results in epigenetic changes in
the placenta and brains of exposed offspring. This is concerning because the placenta plays a key role in fetal
growth and development by mediating fetal nutrition, oxygenation, inflammatory signaling, and transmission of
maternal environmental exposures. Compromises to placental function can adversely affect brain development.
Epigenetic responses to maternal marijuana use likely result in molecular alterations in gene regulation of
offspring developmental trajectories towards neurodevelopmental morbidity, including addiction, autism
spectrum disorder, attention deficit hyperactivity disorder, and cognitive disabilities. Specifically, prenatal THC
exposure is known to alter reward processing, by histone modification of ventral striatal dopaminergic signaling,
affecting addiction vulnerability. However, a mechanistic link between maternal THC use and its impact on
offspring epigenetic regulation of neurodevelopment is impeded by the lack of in vivo longitudinal assessment
secondary to the limitations of current imaging capabilities and feasibility of tissue sampling. We propose to
address this problem by defining a trajectory of perturbed epigenetic regulation following in utero THC exposure
across fetal and early childhood brain and behavioral development. To this end, we will employ three innovative
and complementary approaches using our novel, non-human primate model of chronic maternal THC use: 1)
first-in-kind, longitudinal in vivo imaging of placental and fetal epigenetic regulation and development, 2)
extensive postnatal assessment of infant cognition and behavior, and 3) sophisticated tissue studies confirming
the role of epigenetic modifications in the imaging and behavioral studies. In summary, our study will interrogate
the previously inaccessible mechanistic links underlying the impact of maternal marijuana use on fetal origins of
health, disease and addiction risk. The successful completion of our study will result in 1) new insights into the
impact of maternal THC use on the developing fetal and infant brain, 2) the impact of THC-induced epigenetic
alterations on trajectories of offspring neurodevelopment and behavioral regulation 3) the creation of a
comprehensive, longitudinal in vivo map of offspring epigenetic regulation of neurodevelopment from fetal life to
early childhood, and 4) characterization of ex vivo epigenetic and transcriptomic assessments that can be used
as a reference for other drugs of abuse and environmental exposures. This study has the potential for immediate
translational impact, given the high prevalence of prenatal and postnatal marijuana use and limited data on
longer-term offspring outcomes and contribution to drug addiction. The study’s ultimate goal is to provide
appropriate guidance for women using marijuana who are trying to conceive, are pregnant, or are lactating, and
for clinicians to consider early intervention and screening of offspring exposed prenatally to marijuana.
项目摘要
目前,玛丽莎克是怀孕期间最常用的非法药物。主要的精神活性化合物
大麻,δ-9-四氢大麻酚(THC),可以进入并结合胎盘中的大麻素受体
和胎儿大脑初步数据表明,产前大麻素暴露导致表观遗传变化,
暴露后代的胎盘和大脑这是令人担忧的,因为胎盘在胎儿发育中起着关键作用。
通过调节胎儿营养、氧合、炎症信号和
母体环境暴露。胎盘功能受损会对大脑发育产生不利影响。
对母体大麻使用的表观遗传反应可能导致以下基因调控的分子改变:
后代神经发育疾病的发展轨迹,包括成瘾,自闭症
谱系障碍、注意力缺陷多动障碍和认知障碍。特别是产前四氢大麻酚
已知暴露通过腹侧纹状体多巴胺能信号传导的组蛋白修饰,
影响成瘾的脆弱性然而,母亲使用THC与其对儿童健康的影响之间的机械联系,
后代神经发育的表观遗传调控因缺乏体内纵向评估而受阻
其次是当前成像能力的限制和组织取样的可行性。我们建议
通过定义子宫内THC暴露后受干扰的表观遗传调控轨迹来解决这个问题
在胎儿和儿童早期的大脑和行为发育中的作用。为此,我们将采用三种创新的
和补充方法,使用我们的新的非人灵长类动物模型的慢性母体THC用途:1)
胎盘和胎儿表观遗传调节和发育的同类首次纵向体内成像,2)
对婴儿认知和行为进行广泛的产后评估,以及3)复杂的组织研究证实
表观遗传修饰在成像和行为研究中的作用。总之,我们的研究将询问
以前无法获得的机制联系的影响,母亲使用大麻对胎儿的起源,
健康、疾病和成瘾风险。我们的研究的成功完成将导致1)新的见解,
母亲使用THC对发育中的胎儿和婴儿大脑的影响,2)THC诱导的表观遗传
改变后代神经发育和行为调节的轨迹3)创建一个
从胎儿到成年的神经发育的后代表观遗传调控的全面、纵向体内图谱
幼儿期,以及4)表征可以使用的离体表观遗传和转录组学评估
作为其他药物滥用和环境暴露的参考。这项研究有可能立即
翻译的影响,鉴于产前和产后大麻使用的高流行率和有限的数据,
长期的后代结果和对药物成瘾的贡献。这项研究的最终目标是提供
对正在尝试怀孕、怀孕或哺乳的使用大麻的妇女提供适当的指导,
让临床医生考虑对产前接触大麻的后代进行早期干预和筛查。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Cannabis Use and Perinatal Health-Reply.
大麻使用和围产期健康回复。
- DOI:10.1001/jama.2023.23239
- 发表时间:2024
- 期刊:
- 影响因子:0
- 作者:Lo,JamieO;Hedges,JasonC;Metz,TorriD
- 通讯作者:Metz,TorriD
Cannabis Use in Pregnancy and Neonatal Outcomes: A Systematic Review and Meta-Analysis.
大麻在妊娠和新生儿结局中的使用:系统评价和荟萃分析。
- DOI:10.1089/can.2022.0262
- 发表时间:2024
- 期刊:
- 影响因子:3.8
- 作者:Lo,JamieO;Shaw,Beth;Robalino,Shannon;Ayers,ChelseaK;Durbin,Shauna;Rushkin,MeganC;Olyaei,Amy;Kansagara,Devan;Harrod,CurtisS
- 通讯作者:Harrod,CurtisS
Expectant management of preterm premature rupture of membranes at 34 weeks: a cost effectiveness analysis.
- DOI:10.1080/14767058.2021.2017874
- 发表时间:2022-12
- 期刊:
- 影响因子:1.8
- 作者:Powell, Jacqueline M.;Frank, Zoe C.;Clark, Grace, V;Lo, Jamie O.;Caughey, Aaron B.
- 通讯作者:Caughey, Aaron B.
Impact of Prenatal Cannabis Use Disorder on Perinatal Outcomes.
产前大麻使用障碍对围产期结局的影响。
- DOI:10.1097/adm.0000000000001123
- 发表时间:2023
- 期刊:
- 影响因子:5.5
- 作者:Prewitt,KristinC;Hayer,Sarena;Garg,Bharti;Benson,AshleyE;Hedges,MadelineA;Caughey,AaronB;Lo,JamieO
- 通讯作者:Lo,JamieO
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Jamie Lo其他文献
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{{ truncateString('Jamie Lo', 18)}}的其他基金
Impact of maternal marijuana use on epigenetic regulation of offspring neurodevelopment
母亲吸食大麻对后代神经发育的表观遗传调控的影响
- 批准号:
10506644 - 财政年份:2022
- 资助金额:
$ 52.5万 - 项目类别:
Mechanistic Analysis of Zika Virus Induced Placental Damage During Pregnancy
寨卡病毒引起妊娠期胎盘损伤的机制分析
- 批准号:
10641890 - 财政年份:2019
- 资助金额:
$ 52.5万 - 项目类别:
Understanding the effects of moderate vs. heavy chronic maternal marijuana exposure in a non-human primate model
了解中度与重度慢性母体大麻暴露对非人类灵长类动物模型的影响
- 批准号:
10000192 - 财政年份:2019
- 资助金额:
$ 52.5万 - 项目类别:
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