MicroRNAs as regulators of drug metabolism and transport in pregnant and lactating women

越来越明显的是，表观遗传机制，如微(Mi)RNAs改变了产物 药物受体、代谢酶和药物外排转运体，从而影响治疗剂量和耐药性 和毒性。药物代谢酶和转运蛋白(DMET)的表达和生物利用度改变 在孕妇和哺乳期妇女中观察到，不仅可能影响母亲，而且还可能影响儿童健康 和发展。对这一妊娠生理部位的机制理解以及miRNAs如何靶向 DMET在这两种独特的生活环境中受到调节，这在很大程度上是未被探索的。MicroRNAs是小的、非编码的 通过诱导翻译抑制在转录后水平负向调节基因表达的RNA 或信使核糖核酸的降解。它们由自己的基因或内含子编码，并通过多个阶段成熟 这两个过程都受到孕妇体内尚未破译的各种暴露的控制。在一个 最近，NICHD授予了5个R01HD099091-02，我们正在利用乌干达、津巴布韦和美国的大量人员 女性在识别荷尔蒙和微生物组调节的传递耐药性或 育龄妇女对感染的易感性--这是迄今为止尚未探索的研究领域。在短短一年内 我们在两篇原创文章和国际会议上的一次演讲中发表了结果 逆转录病毒和机会性感染(CROI 2020)。现有的元数据目录包括丰富的人口统计数据 和行为因素、感染状态、全身和粘膜水平的天然免疫生物标志物预测 性传播感染、生物失调和艾滋病毒，以及全身内源性雌二醇孕酮水平 性激素结合球蛋白。目前的R01专注于激素避孕药的使用，因此 将孕妇和哺乳期妇女排除在全球miRNA转录组分析之外，但我们有所有的元数据 适用于这些女性及其纵向样本。对NICHD NOT-HD-20-003的回应建议 利用在母公司R01和 扩大检测范围，以包括孕妇和哺乳期妇女现有的生物检疫，以实现以下目标： 1)确定怀孕和哺乳对调节DMET的有效miRNAs水平的影响；2)探索 生殖激素和微生物组驱动的针对已知胎盘药物的miRNAs的富集化 转运蛋白；3)识别在怀孕或哺乳期间差异表达的已知调节miRNAs 接触抗病毒和抗炎药物，重点是药代动力学研究有限的药物 在这些情况下，新冠肺炎的实验疗法就是例证。拟议的研究将产生 将通过NICHD DASH获得高维数据。它将打开硅胶小说的大门 孕妇和哺乳期妇女药物安全性和可获得性的预测模型将促进我们的机制 了解潜在的药物-药物相互作用，并可能确定药物的创新可修饰因素 在母婴高度脆弱的条件下暴露和新的治疗靶点。

It is becoming increasingly evident that epigenetic mechanisms such as micro (mi) RNAs modify the production of drug receptors, metabolizing enzymes and drug efflux transporters thus affecting therapeutic dose, resistance and toxicity. Altered expression and bioavailability of drug metabolizing enzymes and transporters (DMETs) has been observed in pregnant and lactating women with the potential to affect not only mothers but also child health and development. Mechanistic understanding of this site of pregnancy physiology and how miRNAs targeting DMETs are regulated in these two unique life settings is largely unexplored. MicroRNAs are small, non-coding RNAs that negatively regulate gene expression at the post-transcriptional level by inducing translational inhibition or mRNA degradation. They are encoded by their own genes or within introns and mature through a multistage process, both of which controlled by a variety of exposures not yet deciphered in pregnant women. Under a recently NICHD-awarded 5 R01HD099091-02 we are utilizing large cohorts of Ugandan, Zimbabwean and US women to make inroads in identifying hormonally and microbiome-regulated miRNAs that convey resistance or susceptibility to infection in reproductive age women – an area of research unexplored to date. In just one year of funding we published results in two original articles and a presentation at the international Conference on Retroviruses and Opportunistic Infections (CROI 2020). The extant metadata catalog includes rich demographic and behavioral factors, infection status, systemic and mucosal levels of innate immunity biomarkers predictive of sexually transmitted infections, dysbiosis and HIV, and systemic levels of endogenous estradiol, progesterone and sex-hormone binding globulin. The current R01 is focused on hormonal contraceptive use and therefore has excluded pregnant and lactating women from the global miRNA transcriptome analysis but we have all metadata available for these women and their longitudinal samples. This response to NICHD NOT-HD-20-003 proposes to leverage existing biospecimens, data and technological resources accumulated during the parent R01 and expand testing to include existing biospecimens from pregnant and lactating women toward the following aims: 1) determine effect of pregnancy and breastfeeding on levels of validated miRNAs regulating DMETs; 2) explore reproductive hormones- and microbiome-driven enrichment for miRNAs targeting known placental drug transporters; 3) identify miRNAs differentially expressed during pregnancy or breastfeeding known to regulate exposure to antiviral and anti-inflammatory drugs, with emphasis on drugs with limited pharmacokinetics studies in these conditions exemplified by experimental therapeutics for COVID-19. The proposed research will generate high-dimension data to become available through the NICHD DASH. It will open the door to novel in silico predictive models of drug safety and availability in pregnant and lactating women, will advance our mechanistic understanding of potential drug-drug interactions, and may identify innovative modifiable factors of drug exposure and novel therapeutic targets in highly vulnerable conditions of mother and child.