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

MicroRNA 作为孕妇和哺乳期妇女药物代谢和转运的调节剂

• 批准号: 10177227
• 负责人: RAINA N. FICHOROVA
• 金额: $ 16.88万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-13 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177227
• 关键词: Address; Affect; Age; Anti-Inflammatory Agents; Antiviral Agents; Area; Award; Base Pairing; Behavioral; Biological Availability; Blood Circulation; Breast Feeding; COVID-19; Catalogs; Child; Child Development; Child Health; Clinical; Complex; Contraceptive Usage; Cross-Sectional Studies; Data; Diagnostic; Distant; Dose; Drug Efflux; Drug Exposure; Drug Interactions; Drug Kinetics; Drug Receptors; Drug Targeting; Drug Transport; Drug resistance; Drug toxicity; Environment; Enzymes; Epigenetic Process; Estradiol; Event; Exposure to; Female; Funding; Gene Expression; Gene Silencing; Genes; Genetic Transcription; HIV; Hormonal; Hormones; Infection; International; Introns; Investigational Therapies; Lactation; Life; Maternal Health; Menstrual cycle; Messenger RNA; Metadata; MicroRNAs; Modeling; Molecular; Mothers; Mucous Membrane; National Institute of Child Health and Human Development; Natural Immunity; Opportunistic Infections; Organ; Parents; Pharmaceutical Preparations; Pharmacogenomics; Physiology; Predisposition; Pregnancy; Pregnancy Outcome; Pregnant Women; Process; Progesterone; Proteins; Publishing; RNA Degradation; Research; Resistance; Resources; Retroviridae Infections; Safety; Sampling; Serum; Sex Hormone-Binding Globulin; Sexually Transmitted Diseases; Shotguns; Site; Small RNA; Strategic Planning; Testing; Therapeutic; Tissues; Toxic effect; Translational Repression; Translational Research; Treatment Efficacy; Untranslated RNA; Visit; Woman; cohort; differential expression; drug metabolism; drug production; dysbiosis; epigenetic regulation; evidence base; exosome; extracellular vesicles; hormonal contraception; improved; in silico; innovation; mRNA Transcript Degradation; medication safety; microbiome; microbiome components; microbiome sequencing; multidimensional data; new therapeutic target; novel; predictive marker; predictive modeling; pregnant; reproductive; reproductive hormone; reproductive tract; response; symposium; tool; transcriptome; transcriptomics

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.

越来越明显的是，诸如 micro (mi) RNA 之类的表观遗传机制会改变生产 药物受体、代谢酶和药物外流转运蛋白的影响，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发生改变 在孕妇和哺乳期妇女中观察到，不仅可能影响母亲，还可能影响儿童健康 和发展。对妊娠生理学这一部位的机制理解以及 miRNA 如何靶向 DMET 在这两种独特的生活环境中的调节很大程度上尚未被探索。 MicroRNA 很小，非编码 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 过程，这两者都是由孕妇中尚未破译的各种暴露控制的。下一个 最近 NICHD 授予 5 R01HD099091-02，我们正在利用来自乌干达、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 miRNA 方面取得进展，这些 miRNA 传达了耐药性或 育龄妇女对感染的易感性——迄今为止尚未探索的研究领域。短短一年内 我们在两篇原创文章和国际会议上的演讲中发表了研究结果 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 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、黄体酮的全身水平 和性激素结合球蛋白。目前的 R01 专注于激素避孕药的使用，因此具有 将孕妇和哺乳期妇女排除在全球 miRNA 转录组分析之外，但我们拥有所有元数据 可用于这些女性及其纵向样本。对 NICHD NOT-HD-20-003 的回应建议 利用母公司 R01 期间积累的现有生物样本、数据和技术资源 扩大测试范围，将孕妇和哺乳期妇女的现有生物样本纳入其中，以实现以下目标： 1) 确定怀孕和母乳喂养对调节 DMET 的经过验证的 miRNA 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 miRNA 富集 运输商； 3) 识别在怀孕或母乳喂养期间差异表达的 miRNA，已知其具有调节作用 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，以 COVID-19 的实验疗法为例。拟议的研究将产生 通过 NICHD DASH 可获得高维数据。它将打开电脑小说的大门 孕妇和哺乳期妇女药物安全性和可用性的预测模型将推进我们的机制 了解潜在的药物-药物相互作用，并可能识别药物的创新可改变因素 母亲和儿童高度脆弱的情况下的暴露和新的治疗靶点。