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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：
10337051
负责人：
EDWARD K CHAN
金额：
$ 37.74万
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/10337051
关键词：
Affect Alzheimer&apos s Disease Amyloidosis Autoimmune Diseases Bacteria Biological Assay Biological Markers Biology Cardiovascular Diseases Cells Cellular biology Chronic Clinical Clinical Research Complex Data Dendritic Cells Dental Cementum Dental Plaque Development Disease Disease Management Ecology Endothelium Endotoxins Epithelial Epithelial Cells 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 Inherited Innate Immune Response Journals Kinetics Knockout Mice LDL Cholesterol Lipoproteins Laboratories Ligation Lipopolysaccharides Malignant Neoplasms 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 Prealbumin 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 base clinically relevant conventional therapy crosslink cytokine dysbiosis improved in vivo individual patient innate immune pathways knockout gene mRNA Expression macrophage microbial monocyte mouse model neutrophil novel therapeutics oral cavity epithelium pathogen pathogenic bacteria periodontopathogen rational design recruit response 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