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）RNA修饰的生产 药物受体、代谢酶和药物外排转运蛋白的变化，从而影响治疗剂量、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，而且可能影响儿童健康 发展先行者的要求对妊娠生理学的这一位点的机制理解以及miRNAs如何靶向 DMET在这两种独特的生活环境中受到监管，这在很大程度上尚未探索。MicroRNA是一种小的非编码RNA， 通过诱导翻译抑制在转录后水平负调控基因表达的RNA 或mRNA降解。它们由自己的基因或内含子编码，并通过多阶段成熟。 这两个过程都是由孕妇尚未破译的各种暴露控制的。下 最近，NICHD授予5 R 01 HD 099091 -02，我们正在利用乌干达、津巴布韦和美国的大群 女性在识别传递耐药性的尿道和微生物组调节的miRNA方面取得进展， 育龄妇女易受感染-这是一个迄今尚未探索的研究领域。短短一年时间 我们在两篇原创文章中发表了研究结果，并在国际会议上发表了一份报告， 逆转录病毒和寄生虫感染（CROI 2020）。现存的元数据目录包括丰富的人口统计数据， 行为因素、感染状态、先天免疫生物标志物的全身和粘膜水平 性传播感染，生态失调和艾滋病毒，以及内源性雌二醇，孕酮 和性激素结合球蛋白目前的R 01侧重于激素避孕药的使用，因此， 从全球miRNA转录组分析中排除了孕妇和哺乳期妇女，但我们有所有的元数据， 这些女性及其纵向样本的可用性。对NICHD NOT-HD-20-003的回复建议 利用母公司R 01期间积累的现有生物标本、数据和技术资源， 扩大检测范围，以包括孕妇和哺乳期妇女的现有生物标本，以实现以下目标： 1)确定妊娠和母乳喂养对经验证的调节DMET的miRNA水平的影响; 2）探索 生殖激素和微生物组驱动的靶向已知胎盘药物的miRNA富集 3）识别已知在妊娠或哺乳期间差异表达的调节转运蛋白的miRNA 暴露于抗病毒和抗炎药物，重点是药代动力学研究有限的药物 在COVID-19的实验性治疗中，这项研究将产生 高维数据将通过NICHD DASH提供。它将打开电脑小说的大门 预测模型的药物安全性和可用性在孕妇和哺乳期妇女，将促进我们的机制， 了解潜在的药物相互作用，并可能识别药物的创新可修改因素 暴露和新的治疗目标，在非常脆弱的条件下，母亲和儿童。

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.