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.

项目概要/摘要 此应用程序响应 NOT-DA-20-039：大麻使用和大麻素对发育的影响 大脑。产前吸食大麻很常见，而且还在不断增加，贫困、年轻人、妇女中的比例高达四分之一。 服务不足的女性。大麻合法化的扩大导致了大麻的供应、使用和认知的增加 安全性以及增强的效力。然而，缺乏关于产前使用增加剂量的影响的数据。 大麻对后代神经发育的作用。我们的小组目前正在进行密集的、前瞻性的 母亲产前使用大麻对婴儿神经发育影响的调查（R01DA044504）。我们的 正在进行的研究已经提供了产前大麻对后代生长和影响的初步证据 神经发育，但不涉及对这些背后的基因组途径的全面询问 协会。精确定位基因组途径将使我们能够识别胎儿伤害的生物标志物并开发 保护和治疗暴露后代的新型筛查工具和干预目标。胎盘是一个 调节子宫内环境、母婴沟通（包括胎儿的通道）的独特器官 大麻素——在支持胎儿生长和神经发育方面发挥着关键作用。我们的开创性工作 研究小组发现，产前环境影响胎盘功能，胎盘功能的改变 可以通过胎盘的基因组图谱得知，并且胎盘基因组图谱的改变是相关的 新生儿生长和神经行为。 MicroRNA (miRNA) 是胎盘表观遗传学中尚未被研究的一个方面 规定; miRNA 是短的非编码 RNA，可在转录后调节基因表达，并且对 胎盘和神经发育的调节因子。最近的一项初步研究支持了以下假设：母亲 大麻可能会影响胎盘免疫基因网络和后代焦虑，但并非旨在调查 产前大麻，仅包括少数大麻使用者，并且不包括 miRNA。我们提出一个 全面的胎盘 miRNA 和 mRNA 分析研究以确定产前大麻的影响 暴露胎盘基因组活性和婴儿神经发育。我们检验中心假设 产前接触大麻会导致胎盘内源性大麻素、神经元发育、 免疫和压力信号通路，这些功能基因组特征也会影响婴儿的发育 发展。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）来评估 产前大麻对婴儿神经发育的影响，包括胎盘收集候选甲基- 化验。我们提出的基因组机制研究涉及添加最先进的全转录- 大量 RNA 测序（mRNA 和 miRNA）来描绘产前大麻暴露的功能影响 以及与婴儿发育的联系。确定产前大麻影响的基因组图谱 婴儿发育是及时的，并且有可能识别暴露和后代风险的生物标志物以及 未来干预工作的分子目标。