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
- 来源:
- 关键词:AffectAlzheimer&aposs DiseaseAmyloidosisAutoimmune DiseasesBacteriaBiological AssayBiological MarkersBiologyCardiovascular DiseasesCellsCellular biologyChronicClinicalClinical ResearchComplexDataDendritic CellsDental CementumDental PlaqueDevelopmentDiseaseDisease ManagementEcologyEndotheliumEndotoxinsEpithelialEpithelial CellsFibroblastsForsythiaFusobacterium nucleatumFutureGene ExpressionGenerationsGingivaGingival Crevicular FluidGingival PocketGingivitisGoalsHemophilia AHumanHybridsIRAK4 geneImmune signalingIn VitroIndividualInfectionInflammationInflammatoryInheritedInnate Immune ResponseJournalsKineticsKnockout MiceLDL Cholesterol LipoproteinsLaboratoriesLigationLipopolysaccharidesMalignant NeoplasmsMaxillaMediatingMessenger RNAMicroRNAsModelingMolecular BiologyMusMyelogenousNatural ImmunityOralOsteoblastsOsteoclastsPathogenesisPathway interactionsPatientsPeer ReviewPeptidoglycanPeriodontal DiseasesPeriodontal LigamentPeriodontitisPlayPorphyromonas gingivalisPrealbuminPredispositionProductionProtocols documentationPublishingRegulationReportingResistanceRheumatoid ArthritisRoleSalivaSeriesSeverity of illnessSignal PathwaySignal TransductionSmall RNASpleenStreptococcus gordoniiSystemSystemic diseaseTLR1 geneTLR2 geneTLR4 geneTNF Receptor-Associated FactorsTherapeutic InterventionTimeTissuesToll-Like Receptor PathwayToll-like receptorsTreponema denticolaVirus DiseasesWorkadverse pregnancy outcomealveolar bonebaseclinically relevantconventional therapycrosslinkcytokinedysbiosisimprovedin vivoindividual patientinnate immune pathwaysknockout genemRNA Expressionmacrophagemicrobialmonocytemouse modelneutrophilnovel therapeuticsoral cavity epitheliumpathogenpathogenic bacteriaperiodontopathogenrational designrecruitresponsetherapeutic targettherapy 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
项目成果
期刊论文数量(0)
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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: