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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

基本信息

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
项目类别：
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

项目摘要

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.

它是越来越明显的表观遗传机制，如微（mi） rna修饰生产