The Role of CD4+ Memory T cell Subtypes in Periodontal Disease Recurrence
CD4 记忆 T 细胞亚型在牙周病复发中的作用
基本信息
- 批准号:10642981
- 负责人:
- 金额:$ 16.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:16S ribosomal RNA sequencingAccelerationAcuteAdultAlveolar Bone LossAntigensApoptosisAwardBacteriaBiological AssayBirthCD4 Positive T LymphocytesCD8B1 geneCell CompartmentationCellsCervical lymph node groupChronic DiseaseClinicalComplexDataDevelopmentDiseaseDisease ProgressionDisease modelDown-RegulationFosteringFutureGenerationsGerm-FreeGingivaGoalsGrowthHealthHealth TransitionHumanImmuneImmunologicsImmunologyInflammationInflammatoryInterventionKnowledgeLifeLigatureLinkLiteratureMemoryMetabolicMethodsModelingMucous MembraneMusNational Institute of Dental and Craniofacial ResearchOralOral CharactersPathogenicityPathologicPatientsPeriodontal DiseasesPeriodontitisPhasePhenotypePopulationPostdoctoral FellowPre-Clinical ModelProcessProductivityPropertyPublic HealthRecurrenceRecurrent diseaseRegulatory T-LymphocyteRelapseResearchResearch PersonnelResolutionRoleT cell infiltrationT memory cellT-LymphocyteTestingTherapeuticTimeTissue ExpansionTissuesTooth Lossbonebone losscareercell typecheckpoint inhibitionchronic inflammatory diseaseclinically relevanteffector T cellgerm free conditionhealthy agingin vivo Modelinflammatory bone losslymph nodesmemory CD4 T lymphocytemicrobialmicrobial colonizationmicroorganism antigenmouse modelnoveloral microbiomepreventprogramsresponsespatiotemporaltherapeutic targettranscriptomicstranslational scientisttranslational study
项目摘要
Project Summary
The recurrence of periodontal disease (PD) is a poorly immunologically defined or therapeutically targeted
clinical challenge. Uncovering the homeostatic and pathogenic potential of long-term immune cells in
periodontal tissues is crucial to revealing the cellular drivers of PD recurrence. This proposal focuses on
an overlooked periodontal-associated cellular compartment, CD4+ T memory cells (TM), which can readily
recognize microbial antigens for a quick and robust response. For this purpose, we will utilize a newly
characterized murine model of recurrent PD and a method for gingival T-cell enrichment. In this model,
time is a critical variable for recognizing disease initiation, resolution, and recurrence. By establishing this
model, we will be able to define a “recovered” baseline instead of a “healthy” baseline state, which is more
clinically accurate. Also, it allows defining how multiple relapse episodes incrementally impact the complex
periodontally-associated immune network. The preliminary studies revealed that CD4+ TM developed in the
gingiva soon after birth due to increasing environmental antigenic exposure. While the mice fully recovered
from ligature-induced PD, the bone loss rate accelerated during PD recurrence. Most intriguingly, CD4+ TM
subtypes are enriched in the gingiva during PD recurrence. Gingival CD4+ tissue-resident memory cells
induced bone loss when circulating T cell infiltration was inhibited. Based on these findings, we will test the
hypothesis that the PD-induced generation and persistence of CD4+ TM subtypes determine PD
recurrence. Thus, targeted depletion of these cells by inhibiting metabolic checkpoints will enhance
immune-regulatory responses and inhibit PD recurrence. There are three interconnected but independent
Aims: 1) To identify the spatiotemporal development of CD4+ TM cells in periodontal tissues. Here, the
focus will be on understanding the constitutive and pathologic generation of CD4+ TM cells to determine
their roles in the gingival immune landscape. 2) To elucidate PD-induced CD4+ TM pathogenicity. Here, we
will evaluate which CD4+ TM subtypes retain pro-inflammatory and osteoclastogenic programming after
PD. We will make transcriptomic comparisons between CD4+ TM subtypes and assess the findings with ex
vivo functional assays to validate their pathogenic potential. 3) To develop an intervention strategy for CD4+
TM depletion to prevent PD recurrence. Here, we will employ a metabolic-based strategy to selectively
deplete PD-induced CD4+ TM and enhance regulatory T cells enrichment to prevent PD recurrence. The
independence award (PAR-22-041) will foster my independent research growth and allow me to accomplish
my long-term career goal to become a productive, independent translational scientist in periodontology and
related fields focused on chronic diseases’ recurrence.
项目总结
项目成果
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Carla Alvarez Rivas其他文献
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