Clinical Research of Oral Connective Tissue Program
Clinical Research of Oral Connective Tissue Program
批准号:
9359804
负责人:
Martha Somerman
金额:
$17.58万
依托单位国家:
美国
项目类别:
财政年份:
--
资助国家:
美国
项目状态:
未结题
起止时间:
至
关键词:
AffectAgeAlveolar Bone LossAmino AcidsBindingBinding SitesBiological AssayBlood specimenBrazilC-terminalCHS proteinCandidate Disease GeneCase StudyCellsCervicalClinicClinicalClinical DataClinical ResearchCo-ImmunoprecipitationsCollaborationsConnective TissueDataDaughterDentalDental cariesDevelopmentDiagnosisDiseaseElectrophoretic Mobility Shift AssayEscherichia coliExhibitsExtramural ActivitiesFibroblastsFusobacterium nucleatumGene ProteinsGenesGenetic Predisposition to DiseaseGingivaGoalsGram-Negative BacteriaHemorrhageHeterodimerizationHumanIFN consensus sequence binding proteinImmuneIn VitroIndividualInfectionInflammationInflammatory ResponseInstitutional Review BoardsKnockout MiceLiteratureMaintenanceManuscriptsMapsMediatingMedical HistoryMetabolic DiseasesMicrobial BiofilmsMissense MutationMolecular AnalysisMusMutationN-terminalNational Institute of Dental and Craniofacial ResearchNatural HistoryNatural regenerationOralOsteoclastsPathologyPatientsPatternPeriodontal DiseasesPeriodontal LigamentPeriodontitisPhenotypePhosphorylationPhosphoserine MotifPlayPredispositionProteinsProtocols documentationReportingRepressionResearchResearch PersonnelRoleRoot ResorptionSalivaSalivarySamplingSchool DentistrySerineSonTissuesTooth eruptionTooth root structureTooth structureUnited States National Institutes of HealthUniversitiesWorkbasebone metabolismcalcificationchediak-higashi syndromecraniofacial complexdisease-causing mutationexome sequencinggenome-widehealthy volunteerinfancykindredmacrophagemembermicroCTmineralizationmutantnovelnuclear factors of activated T-cellsoral statusoral tissueosteoclastogenesisprobandprogramsprotein foldingrepairedresponsetranscription factortranscriptome sequencingvector
中文摘要
项目a:确定遗传易感性和促进特发性牙根吸收的免疫病理机制。具体来说,描述IRF8突变在增加多发性特发性根吸收易感性中的作用
英文摘要
Project A. Determine the genetic susceptibility and immunopathological mechanisms contributing to idiopathic tooth root resorption. Specifically, delineate the role of IRF8 mutations in increased susceptibility to multiple idiopathic root resorption
During our research of the Bsp KO mice, we identified an idiopathic tooth root resorption phenotype. Based on this finding, salivary samples were obtained from individuals with idiopathic root resorption (and appropriate controls) for whole exome sequencing because previous case reports of familial pattern suggested a genetic susceptibility to the disease. Following IRB approval from the University of Detroit Mercy School of Dentistry and the National Institutes of Health (NIH), dental/medical histories, x-rays, saliva samples, and extracted teeth were collected from a kindred (3 affected and 3 unaffected members) exhibiting idiopathic root resorption. On examination, the proband and the affected son and daughter exhibited severe root resorption of multiple teeth, but had no other significant medical history. Micro-CT of exfoliated teeth revealed a unique pattern of severe cervical root resorption distinct from tooth decay. Whole exome sequencing performed using saliva identified SNPs in twenty-three candidate genes that co-segregated with the resorption phenotype, including a novel autosomal dominant missense mutation in Interferon Regulatory Factor 8 (IRF8). In another independent study using blood samples by our collaborator, Dr. Steve Holland, a novel mutation in IFR8 was identified. Both Kindreds exhibited chronic periodontitis and/or multiple idiopathic root resorption, with two novel autosomal dominant heterozygous mutations in the highly conserved N-terminal (T96M, Holland)) and C-terminal (G388S, Neely) motifs of IRF8. Primarily expressed in immune cells, IRF8 is a key regulator of inflammation and bone metabolism, and its repression mediates osteoclastogenesis by enhancing nuclear factor of activated T cells c1 (NFATc1) activity. The identified amino acid change (G388S) in IRF8 was localized to a highly conserved C-terminal motif, leading to altered serine phosphorylation motifs and phosphoserine binding domains, and is predicted to cause a large shift in 3D protein folding. These data suggest that the G388S mutation would impair IRF8 heterodimerization with other transcription factors including NFATc1, thereby producing overactive osteoclasts that target the periodontia. Consistent with these predictions, we noted that compared to WT mice, Irf8-/- mice exhibited increased osteoclast activity in the periodontia, widened periodontal ligament (PDL) space, and accelerated alveolar bone loss.
Ongoing: In collaboration with Drs. Ozato and Holland, we are characterizing the periodontal phenotype in Irf8 KO mice and patients with IRF8 mutations. WT and human IRF8 mutant constructs will be expressed (already initiated) in Irf8 KO macrophages to map genome-wide IRF8 mutant binding sites and profile differentially regulated genes using ChIP/ChIPseq and RNAseq. In preliminary studies, we reported a 3-fold increase in osteoclast numbers with mutant human IRF8G388S vector transduced into Irf8-/- macrophages compared to IRF8WT. Other ongoing assays include co-immunoprecipitation and Electrophoretic Mobility Shift Assays (EMSA), osteoclast differentiation and function assays, and characterization of Irf8 KO mouse phenotype.
Project B. Disorders of mineralization: In collaboration with NIDCR clinical researchers and other IC clinicians, we have been examining individuals with mineralized tissue metabolism disorders for alterations in tissues/cells of the DOC complex. In addition, we have been seeing patients with mutations in ENPP1, a PPi regulator, with mutations causing generalized arterial calcification of infancy (GACI) to determine if there is a dental phenotype. Initial observations indicated delayed tooth eruption.
Project C. Chediak-Higashi Syndrome (CHS): Individuals with CHS, a rare autosomal recessive disease caused by mutations in the gene encoding lysosomal trafficking regulator, are immunodeficient, resulting in increased susceptibility to infections impacting several tissues, including oral tissues. In our ongoing collaboration with Drs. Nociti and Kantovitz from the State University of Campinas Brazil, seven CHS-diagnosed individuals (four atypical and three classic, ages 8-21) were comprehensively examined regarding their oral status in the NIH clinic, and gingival fibroblasts (GF) were obtained from atypical and classic CHS patients and control individuals. Clinical data indicated increased bleeding and probing depths of periodontal tissues vs periodontal tissues from healthy volunteers and more bleeding for atypical vs classic patients, yet the severe periodontal disease reported in the literature was not apparent. In vitro studies performed to date, reveal a different profile for atypical vs control cells at baseline and also when challenged with E. coli LPS and F. nucleatum extract. Data from qPCR and multiplex protein analyses suggest that gingival fibroblasts from atypical patients exhibit an altered response to LPS suggestive of a more robust pro-inflammatory response to dental biofilm, and that higher levels of TLR-4 in atypical CHS GF play a key role in a hyperactive periodontal response to gram-negative bacteria (manuscript under review,2016).
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Laboratory of Oral Connective Tissue Biology
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批准号:8939439
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项目类别:
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资助金额:$110.7万
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财政年份:--
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负责人:Martha Somerman
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依托单位:
Laboratory of Oral Connective Tissue Biology
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批准号:9155481
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项目类别:
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资助金额:$107.1万
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财政年份:--
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负责人:Martha Somerman
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依托单位:
Laboratory of Oral Connective Tissue Biology
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批准号:10244802
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项目类别:
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资助金额:$101.32万
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财政年份:--
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负责人:Martha Somerman
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依托单位:
Clinical Research of Oral Connective Tissue Program
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批准号:10244803
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项目类别:
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资助金额:$17.88万
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财政年份:--
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负责人:Martha Somerman
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依托单位:
Laboratory of Oral Connective Tissue Biology
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批准号:8750651
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项目类别:
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资助金额:$106.61万
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财政年份:--
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负责人:Martha Somerman
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依托单位:
Clinical Research of Oral Connective Tissue Program
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批准号:8939440
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项目类别:
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资助金额:$19.53万
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财政年份:--
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负责人:Martha Somerman
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依托单位:
Laboratory of Oral Connective Tissue Biology
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批准号:9359803
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项目类别:
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资助金额:$99.6万
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财政年份:--
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负责人:Martha Somerman
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依托单位:
Clinical Research of Oral Connective Tissue Program
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批准号:10006390
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项目类别:
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资助金额:$17.88万
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财政年份:--
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负责人:Martha Somerman
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依托单位:
Clinical Research of Oral Connective Tissue Program
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批准号:8750652
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项目类别:
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资助金额:$18.81万
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财政年份:--
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负责人:Martha Somerman
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依托单位:
Laboratory of Oral Connective Tissue Biology
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批准号:10006389
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项目类别:
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资助金额:$101.32万
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财政年份:--
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负责人:Martha Somerman
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依托单位:
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