Placental Genomics in the Developmental Consequences of Marijuana Use in Pregnancy

项目摘要/摘要 本申请响应NOT-DA-20-039：大麻使用和大麻素对发育的影响- 脑筋急转弯。产前大麻的使用很普遍，而且还在增加，穷人、年轻人和 服务不足的女性。扩大大麻合法化导致了更多的可获得性、使用率、对 安全性和增强的效力。然而，缺乏关于产前使用增强剂的影响的数据。 ED-效力大麻对子代神经发育的影响。我们小组目前正在进行一项密集的、前瞻性的 孕妇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产生了初步证据表明，产前大麻对后代的生长发育和 神经发育，但不涉及对这些基因途径的全面询问 联想。精确定位基因组途径将使我们能够识别胎儿损伤的生物标记物并开发 新的筛查工具和干预目标，以保护和治疗暴露的后代。胎盘是一种 调节宫内环境、母胎沟通的独特器官--包括通过 大麻素--在支持胎儿生长和神经发育方面起着关键作用。我们的开创性工作 研究小组透露，产前环境会影响胎盘功能，胎盘功能的改变 可以通过胎盘的基因组图谱得到信息，并且胎盘基因组图谱的变化是相关的 对新生儿生长和神经行为的影响。MicroRNAs(MiRNAs)是胎盘表观遗传学研究较少的一个方面 MiRNAs是一种短的非编码RNA，它在转录后调节基因的表达，并且是临界的。 胎盘和神经发育的生理调节器。最近的一项初步研究支持这样的假设，即母体 大麻可能会影响胎盘免疫基因网络，以及后代焦虑，但并不是为了调查 仅包括少量吸食大麻者，不包括miRNA。我们提出了一个 全面的胎盘miRNA和信使核糖核酸图谱研究以确定产前大麻的影响 胎盘基因组活性与婴儿神经发育的暴露。我们检验了中心假设 产前接触大麻会导致胎盘内源性大麻素、神经元发育、 免疫和应激信号通路，以及这些功能基因组特征也将影响婴儿的变性 发展。我们利用我们正在进行的队列(n=100名吸食大麻者，n=100名非吸食大麻者)评估 产前大麻对婴儿神经发育的影响以及对候选甲基-甲胎盘收集的影响 化验结果。我们建议的基因组机制研究涉及添加最先进的完整转录- Tome RNA测序(mRNA和miRNA)描述产前大麻暴露对功能的影响 并与婴儿发育有关。确定产前大麻对人类健康影响的基因组图谱 婴儿发育是及时的，并提供了识别暴露和后代风险的生物标记物以及 未来干预努力的分子靶点。

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.