Dominant microRNAs as biomarkers in innate immunity and periodontitis

主要 microRNA 作为先天免疫和牙周炎生物标志物

基本信息

  • 批准号:
    10337051
  • 负责人:
  • 金额:
    $ 37.74万
  • 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:
    2019-12-01 至 2024-11-30
  • 项目状态:
    已结题

项目摘要

Abstract Periodontal disease affects millions of individuals in the US alone and has been substantiated as a precursor to other debilitating systemic diseases, including cardiovascular disease, Alzheimer’s disease, rheumatoid arthritis, and adverse pregnancy outcomes. Our laboratories have shown that expression of certain microRNAs (miRNAs) are elevated in murine polymicrobial periodontitis. The current paradigm is that miRNAs are generally involved in fine-tuning gene expression. However, our in vitro studies have demonstrated that miR- 146a is a dominant miRNA that can be up-regulated 30 to 200+ fold during lipopolysaccharide stimulation and, more importantly, that this increase is sustained for days. We have demonstrated that miR-146a is a key regulator in endotoxin-induced tolerance and cross-tolerance using a monocyte/macrophage-based system. Similarly, we have demonstrated that miR-132 is a dominant miRNA in peptidoglycan-stimulated monocytes and can induce cross-tolerance. In the current proposal, these dominant miRNAs will be examined using in vitro and in vivo systems to critically determine their role in our established murine model of periodontitis with 4 major well-characterized periodontal pathogens (Porphyromonas gingivalis, Treponema denticola, Tannerella forsythia, Fusobacterium nucleatum) and Streptococcus gordonii as early colonizer. The overall hypothesis is that these miRNAs are the dominant miRNAs regulating toll-like receptor (TLR)/IL-1-signaling pathways. Four Specific Aims are proposed. Specific Aim 1 will define the mechanistic role of these miRNAs, including mapping of target mRNAs, in primary human oral epithelial cells in reference to human monocytes. Specific Aim 2 will determine the expression kinetics of the dominant miRNA in mono- or time-sequential polymicrobial infection-induced periodontitis in mice and examine the relative effects of TLR2 and TLR4 using gene knockout mice. Specific Aim 3 will evaluate the relative contribution of these dominant miRNAs in this periodontitis model using specific miRNA knockout mice. Specific Aim 4 will investigate the association of these dominant miRNAs as biomarkers in gingival crevicular fluid and gingival tissues in chronic periodontitis and correlation with therapeutic outcomes. The long-term goal is to determine how extensively these dominant miRNAs can serve as functional biomarkers and they regulate innate immune response pathways contributing to periodontitis. In future studies, this mouse periodontitis model will become critical to help develop manipulation of these miRNA functions and/or the TLR pathway into novel therapeutics for periodontitis. Since innate immune response is known to play critical roles in many other diseases, our findings will likely be applicable to other chronic inflammatory and autoimmune diseases.
摘要

项目成果

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EDWARD K CHAN其他文献

EDWARD K CHAN的其他文献

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{{ truncateString('EDWARD K CHAN', 18)}}的其他基金

Dominant microRNAs as biomarkers in innate immunity and periodontitis
主要 microRNA 作为先天免疫和牙周炎生物标志物
  • 批准号:
    10529344
  • 财政年份:
    2019
  • 资助金额:
    $ 37.74万
  • 项目类别:
Dominant microRNAs as biomarkers in innate immunity and periodontitis
主要 microRNA 作为先天免疫和牙周炎生物标志物
  • 批准号:
    10063992
  • 财政年份:
    2019
  • 资助金额:
    $ 37.74万
  • 项目类别:
International Workshop on Autoantibodies & Autoimmunity
自身抗体国际研讨会
  • 批准号:
    7059282
  • 财政年份:
    2005
  • 资助金额:
    $ 37.74万
  • 项目类别:
APPLIED BISYSTEMS PRISM 3100 GENETIC ANALYZER
APPLIED BISYSTEMS PRISM 3100 遗传分析仪
  • 批准号:
    6440153
  • 财政年份:
    2002
  • 资助金额:
    $ 37.74万
  • 项目类别:
Novel Proteins Associated with SS-A/Ro in Target Organs
靶器官中与 SS-A/Ro 相关的新型蛋白质
  • 批准号:
    6632306
  • 财政年份:
    2001
  • 资助金额:
    $ 37.74万
  • 项目类别:
Antigens of the RNA-induced silencing complex in autoimmunity
自身免疫中RNA诱导的沉默复合物的抗原
  • 批准号:
    7336803
  • 财政年份:
    2001
  • 资助金额:
    $ 37.74万
  • 项目类别:
Antigens of the RNA-induced silencing complex in autoimmunity
自身免疫中RNA诱导的沉默复合物的抗原
  • 批准号:
    7560044
  • 财政年份:
    2001
  • 资助金额:
    $ 37.74万
  • 项目类别:
Novel Proteins Associated with SS-A/Ro in Target Organs
靶器官中与 SS-A/Ro 相关的新型蛋白质
  • 批准号:
    6708357
  • 财政年份:
    2001
  • 资助金额:
    $ 37.74万
  • 项目类别:
Antigens of the RNA-induced silencing complex in autoimmunity
自身免疫中RNA诱导的沉默复合物的抗原
  • 批准号:
    7740863
  • 财政年份:
    2001
  • 资助金额:
    $ 37.74万
  • 项目类别:
Novel Proteins Associated with SS-A/Ro in Target Organs
靶器官中与 SS-A/Ro 相关的新型蛋白质
  • 批准号:
    6855774
  • 财政年份:
    2001
  • 资助金额:
    $ 37.74万
  • 项目类别:
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