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:
  • 金额:
    $ 16.88万
  • 依托单位:
  • 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

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

项目成果

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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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RAINA N. FICHOROVA其他文献

RAINA N. FICHOROVA的其他文献

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{{ truncateString('RAINA N. FICHOROVA', 18)}}的其他基金

Molecular Antecedents of Miscarriage
流产的分子前因
  • 批准号:
    10366840
  • 财政年份:
    2022
  • 资助金额:
    $ 16.88万
  • 项目类别:
Molecular Antecedents of Miscarriage
流产的分子前因
  • 批准号:
    10686808
  • 财政年份:
    2022
  • 资助金额:
    $ 16.88万
  • 项目类别:
MicroRNA Predictors of HIV Risk in Reproductive Age Women
育龄妇女 HIV 风险的 MicroRNA 预测因子
  • 批准号:
    10376860
  • 财政年份:
    2019
  • 资助金额:
    $ 16.88万
  • 项目类别:
MicroRNA Predictors of HIV Risk in Reproductive Age Women
育龄妇女 HIV 风险的 MicroRNA 预测因子
  • 批准号:
    10611410
  • 财政年份:
    2019
  • 资助金额:
    $ 16.88万
  • 项目类别:
MicroRNA Predictors of HIV Risk in Reproductive Age Women
育龄妇女 HIV 风险的 MicroRNA 预测因子
  • 批准号:
    9795702
  • 财政年份:
    2019
  • 资助金额:
    $ 16.88万
  • 项目类别:
Innate immunity predictors of HIV: the role of contraception, pregnancy and HSV-2
HIV 的先天免疫预测因素:避孕、怀孕和 HSV-2 的作用
  • 批准号:
    8735981
  • 财政年份:
    2013
  • 资助金额:
    $ 16.88万
  • 项目类别:
Innate immunity predictors of HIV: the role of contraception, pregnancy and HSV-2
HIV 的先天免疫预测因素:避孕、怀孕和 HSV-2 的作用
  • 批准号:
    8897178
  • 财政年份:
    2013
  • 资助金额:
    $ 16.88万
  • 项目类别:
Innate immunity predictors of HIV: the role of contraception, pregnancy and HSV-2
HIV 的先天免疫预测因素:避孕、怀孕和 HSV-2 的作用
  • 批准号:
    8588238
  • 财政年份:
    2013
  • 资助金额:
    $ 16.88万
  • 项目类别:
T. vaginalis viruses as mucosal immunity modifiers with impact on women's health
阴道毛滴虫病毒作为粘膜免疫调节剂对女性健康有影响
  • 批准号:
    8494163
  • 财政年份:
    2012
  • 资助金额:
    $ 16.88万
  • 项目类别:
T. vaginalis viruses as mucosal immunity modifiers with impact on women's health
阴道毛滴虫病毒作为粘膜免疫调节剂对女性健康有影响
  • 批准号:
    7832182
  • 财政年份:
    2010
  • 资助金额:
    $ 16.88万
  • 项目类别:

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激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
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