Placental Genomics in the Developmental Consequences of Marijuana Use in Pregnancy

胎盘基因组学对妊娠期吸食大麻发育后果的影响

• 批准号: 10680973
• 负责人: Todd M Everson
• 金额: $ 60.38万
• 依托单位: MIRIAM HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680973
• 关键词: Address; Affect; Anxiety; Architecture; Biological; Biological Assay; Biological Markers; Birth; Birth Weight; Brain; Cannabinoids; Cannabis; Cannabis sativa plant; Child Development; Collection; Communication; Data; Development; Drug usage; Endocannabinoids; Energy Metabolism; Environment; Epidemiologic Methods; Epigenetic Process; Evaluation; Fetal Growth; Future; Gene Expression; Genes; Genetic Transcription; Genomics; Goals; Growth; Health; Human; Immune; Infant; Infant Development; Intervention; Investigation; Legal; Link; Marijuana; Mediation; Medical; Messenger RNA; Metabolic; Methods; Methylation; MicroRNAs; Molecular; Molecular Target; Mothers; National Institute of Drug Abuse; Neurologic; Neurons; Newborn Infant; Organ; Outcome; Pathway interactions; Perception; Placenta; Play; Pregnancy; Pregnant Women; Prevalence; Regulation; Reporting; Research; Risk; Role; Safety; Sampling; Screening procedure; Seminal; Signal Pathway; Signal Transduction; Strategic Planning; Stress; Surgeon; System; Testing; United States National Academy of Sciences; Untranslated RNA; Vascularization; Woman; Work; addiction; adipokines; biological adaptation to stress; biomarker identification; brain tissue; cohort; design; epigenetic regulation; fetal; fetal marijuana exposure; fetal tobacco exposure; functional genomics; gene network; genome-wide; genomic profiles; high risk population; immune function; implantation; improved; in utero; infant outcome; intrauterine environment; marijuana legalization; marijuana use; marijuana use in pregnancy; marijuana user; maternal marijuana use; miRNA expression profiling; neurobehavior; neurobehavioral; neuroblastoma cell; neurodevelopment; neuron development; new therapeutic target; novel; offspring; phenotypic data; posttranscriptional; pregnant; prenatal; prenatal exposure; prenatal influence; prospective; sperm cell; substance use; transcriptome; transcriptome sequencing; transcriptomic profiling; transcriptomics; trend

PROJECT SUMMARY/ABSTRACT This application is responsive to NOT-DA-20-039: Effects of Cannabis Use and Cannabinoids on the Devel- oping Brain. Prenatal cannabis use is common and increasing, with rates as high as 1 in 4 in poor, young, underserved women. Expanding legalization of cannabis has led to increasing availability, use, perceptions of safety as well as increased potency. However, data is lacking regarding the impact of prenatal use of increase- ed-potency cannabis on offspring neurodevelopment. Our group is currently conducting an intensive, prospective investigation of the impact of maternal prenatal cannabis use on infant neurodevelopment (R01DA044504). Our ongoing study has yielded preliminary evidence for an impact of prenatal cannabis on offspring growth and neurodevelopment, but does not involve a comprehensive interrogation of genomic pathways underlying these associations. Pinpointing genomic pathways will allow us to identify biomarkers of fetal harm and develop novel screening tools and intervention targets to protect and treat exposed offspring. The placenta is a unique organ that regulates the intrauterine environment, maternal-fetal communication--including passage of cannabinoids--and plays a critical role in supporting fetal growth and neurodevelopment. Seminal work by our group has revealed that the prenatal environment impacts placenta function, that alterations in placenta function can be informed by genomic profiling of the placenta, and that alterations in placenta genomic profiles are linked to newborn growth and neurobehavior. MicroRNAs (miRNAs) are an understudied aspect of placenta epigenetic regulation; miRNAs are short non-coding RNAs that regulate gene expression post-transcriptionally and are crit- ical regulators of placental- and neuro-development. A recent initial study supports the hypothesis that maternal cannabis may impact placenta immune gene networks, and offspring anxiety, but was not designed to investigate prenatal cannabis, only included a small number of cannabis users, and did not include miRNA. We propose a comprehensive placenta miRNA and mRNA profiling study to define the impact of prenatal cannabis exposure on placenta genomic activity and infant neurodevelopment. We test the central hypothesis that prenatal cannabis exposure leads to unique alterations in placenta endocannabinoid, neuronal development, immune, and stress signaling pathways, and that these functional genomic features will also impact infant de- velopment. We leverage our ongoing cohort (n=100 cannabis users, n=100 non-users) designed to assess the impact of prenatal cannabis on infant neurodevelopment and including placenta collection for candidate methyl- ation assays. Our proposed genomic mechanisms study involves the addition of state-of-the-art whole transcrip- tome RNA-sequencing (mRNA and miRNA) to delineate the functional impacts of prenatal cannabis exposure and links to infant development. Determining genomic profiles underlying the impact of prenatal cannabis on infant development is timely and offers potential to identify biomarkers of exposure and offspring risk as well as molecular targets for future intervention efforts.

项目总结/摘要 本申请是对NOT-DA-20-039：大麻使用和大麻素对发展的影响的响应。 我的大脑。产前使用大麻很常见，而且越来越多，在贫穷、年轻、 服务不足的女性大麻合法化的扩大导致大麻的供应、使用、对大麻的看法 安全性以及增加的效力。然而，缺乏关于产前使用增加的影响的数据- 大麻对后代神经发育的影响我们的团队目前正在进行一次密集的，前瞻性的 研究母体产前使用大麻对婴儿神经发育的影响（R 01 DA 044504）。我们 正在进行的一项研究已经获得了产前大麻对后代生长影响的初步证据， 神经发育，但不涉及这些基因组通路的基础上的全面审讯 协会.精确定位基因组通路将使我们能够识别胎儿伤害的生物标志物， 新的筛选工具和干预目标，以保护和治疗暴露的后代。胎盘是一种 调节子宫内环境的独特器官，母胎交流-包括通过 大麻素-并在支持胎儿生长和神经发育中起着关键作用。我们的种子工作 研究小组发现，产前环境影响胎盘功能， 可以通过胎盘的基因组图谱来了解，胎盘基因组图谱的改变与 新生儿的生长和神经行为。microRNAs（miRNAs）是胎盘表观遗传学研究不足的方面。 调控; miRNAs是短的非编码RNA，在转录后调节基因表达，并且是关键的。 胎盘和神经发育的生理调节因子。最近的一项初步研究支持了这一假设， 大麻可能会影响胎盘免疫基因网络和后代的焦虑，但不是为了调查 产前大麻，仅包括少量大麻使用者，不包括miRNA。我们提出了一个 全面的胎盘miRNA和mRNA谱研究，以确定产前大麻的影响 胎盘基因组活动和婴儿神经发育。我们检验了中心假设， 产前大麻暴露导致胎盘内源性大麻素，神经元发育， 免疫和应激信号通路，这些功能性基因组特征也将影响婴儿的发育。 - 谢谢我们利用我们正在进行的队列（n=100名大麻使用者，n=100名非使用者），旨在评估 产前大麻对婴儿神经发育的影响， 测定。我们提出的基因组机制研究涉及添加最先进的全转录， 托姆RNA测序（mRNA和miRNA），以描述产前大麻暴露的功能影响 与婴儿发育的联系确定产前大麻对胎儿的影响的基因组特征 婴儿发育是及时的，并提供了确定暴露和后代风险的生物标志物的潜力， 分子靶点作为未来的干预措施。