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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：
10529344
负责人：
EDWARD K CHAN
金额：
$ 38.13万
依托单位：
UNIVERSITY OF FLORIDA
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

来源：
https://reporter.nih.gov/project-details/10529344
关键词：
Affect Alzheimer&apos s Disease Autoimmune Diseases Bacteria Biological Assay Biological Markers Biology Cardiovascular Diseases Cells Cellular biology Clinical Clinical Research Complex Data Dendritic Cells Dental Cementum Dental Plaque Development Disease Disease Management Ecology Endothelium Endotoxins Epithelial Cells Epithelium Familial Amyloid Neuropathies Fibroblasts Forsythia Fusobacterium nucleatum Future Gene Expression Generations Gingiva Gingival Crevicular Fluid Gingival Pocket Gingivitis Goals Hemophilia A Human Hybrids IRAK4 gene Immune signaling In Vitro Individual Infection Inflammation Inflammatory Innate Immune Response Journals Kinetics Knockout Mice LDL Cholesterol Lipoproteins Laboratories Ligation Lipopolysaccharides Macrophage Malignant Neoplasms Maps Maxilla Mediating Messenger RNA MicroRNAs Modeling Molecular Biology Mus Myelogenous Natural Immunity Oral Osteoblasts Osteoclasts Pathogenesis Pathway interactions Patients Peer Review Peptidoglycan Periodontal Diseases Periodontal Ligament Periodontitis Play Porphyromonas gingivalis Predisposition Production Protocols documentation Publishing Regulation Reporting Resistance Rheumatoid Arthritis Role Saliva Series Severity of illness Signal Pathway Signal Transduction Small RNA Spleen Streptococcus gordonii System Systemic disease TLR1 gene TLR2 gene TLR4 gene TNF Receptor-Associated Factors Therapeutic Intervention Time Tissues Toll-Like Receptor Pathway Toll-like receptors Treponema denticola Virus Diseases Work adverse pregnancy outcome alveolar bone chronic inflammatory disease clinically relevant conventional therapy crosslink cytokine dysbiosis improved in vivo individual patient innate immune pathways knockout gene mRNA Expression microbial monocyte mouse model neutrophil novel therapeutics oral cavity epithelium pathogen pathogenic bacteria periodontopathogen rational design recruit response therapeutic miRNA therapeutic target therapy outcome

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.

摘要仅在美国就有数百万人患上牙周病，其他使人衰弱的全身性疾病，包括心血管疾病、阿尔茨海默病、类风湿性关节炎、关节炎和不良妊娠结局。我们的实验室已经证明某些microRNA的表达在鼠多微生物牙周炎中，微RNA（miRNAs）升高。目前的范式是，通常参与基因表达的微调。然而，我们的体外研究表明，miR- 146 a是一种显性的miRNA，在脂多糖刺激期间可以上调30至200+倍，更重要的是，这种增长持续了好几天。我们已经证明了miR-146 a是一个关键，使用基于单核细胞/巨噬细胞的系统，研究内毒素诱导的耐受性和交叉耐受性的调节剂。类似地，我们已经证明miR-132是肽聚糖刺激的单核细胞中的主要miRNA 并能诱导交叉耐受。在目前的建议中，这些占主导地位的miRNAs将使用体外和体内系统，以严格确定它们在我们建立的小鼠牙周炎模型中的作用，主要的特征性牙周病原体（牙龈卟啉单胞菌、齿垢密螺旋体、坦纳氏菌革兰氏阴性杆菌、具核梭杆菌）和戈登链球菌作为早期定殖者。总的假设是这些miRNAs是调节Toll样受体（TLR）/IL-1信号通路的主要miRNAs。四提出了具体目标。具体目标1将定义这些miRNA的机制作用，包括在原代人口腔上皮细胞中相对于人单核细胞的靶mRNA的定位。具体目的2将确定单一或时间顺序的多微生物中优势miRNA的表达动力学，感染诱导的小鼠牙周炎，并使用基因敲除检测TLR 2和TLR 4的相对作用小鼠具体目标3将评估这些显性miRNA在该牙周炎模型中的相对贡献使用特定的miRNA敲除小鼠。Specific Aim 4将研究这些显性miRNAs之间的关联，作为生物标志物在慢性牙周炎龈沟液和牙龈组织中的表达及其与治疗结果。长期目标是确定这些占主导地位的miRNAs在多大程度上可以发挥作用，作为功能性生物标志物，它们调节导致牙周炎的先天免疫应答途径。在在未来的研究中，这种小鼠牙周炎模型将成为帮助开发这些miRNA操作的关键功能和/或TLR途径转化为牙周炎的新疗法。由于先天免疫反应是已知在许多其他疾病中起关键作用，我们的发现可能适用于其他慢性疾病。炎症和自身免疫性疾病。