PGRP3 is a crucial mediator of periodontitis

PGRP3是牙周炎的重要介质

• 批准号: 10441598
• 负责人: Sivaraman Prakasam
• 金额: $ 15.4万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10441598
• 关键词: 16S ribosomal RNA sequencing; Address; Adult; Affect; Affinity; Alveolar Bone Loss; American; Anti-Inflammatory Agents; Atherosclerosis; Attention; Automobile Driving; Bacteria; Binding; Biological Assay; Biological Markers; Biological Models; Biology; Cell Culture Techniques; Cell Separation; Cells; Chronic; Clinical; Communicable Diseases; Data; Dental Plaque; Development; Diabetes Mellitus; Diagnosis; Disease; Environment; Epithelial Cells; Event; Exhibits; Experimental Models; Feedback; Financial Hardship; Flow Cytometry; Fluorescent Antibody Technique; Future; Genetic; Genetic Polymorphism; Genetic Transcription; Gingiva; Gingivitis; Health; Homeostasis; Human; Hypertension; Immune; Immune response; Immunohistochemistry; Immunologic Surveillance; In Situ; In Vitro; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interferons; Knock-out; Knockout Mice; Knowledge; Literature; Mediator of activation protein; Microbe; Mission; Modeling; Monitor; Mucous Membrane; Natural Killer Cells; Oral; Organism; Osteolysis; Pathway interactions; Pattern recognition receptor; Periodontitis; Population; Prevalence; Production; Protein Isoforms; Proteins; Public Health; Recombinants; Regulation; Reporting; Research; Role; Saliva; Sampling; Signal Transduction; Skin; Suspensions; Symbiosis; Techniques; Testing; Time; Tissue Sample; Tissues; Tooth Loss; United States National Institutes of Health; base; chronic inflammatory disease; design; disease phenotype; dysbiosis; experimental study; functional status; gut dysbiosis; human disease; human tissue; immunoregulation; in vivo; innovation; insight; macrophage; microbial; microbial community; microbiome; microbiota; mouse model; novel; novel diagnostics; novel therapeutics; oral microbiome; peptidoglycan recognition protein; population based; receptor; single-cell RNA sequencing; skin microbiome; subgingival microbiota; transcriptome; transcriptomics

PROJECT SUMMARY Periodontitis (PD) is one of the most prevalent chronic infectious diseases that causes osteolysis of alveolar bone and tooth loss. It is estimated that over 47% of the American adult population have some form of PD. In adults >65, this prevalence increases to >70%, which is three times the prevalence of diabetes, and higher than that of atherosclerosis or hypertension. The financial burden associated with PD is estimated to be >$10.5 billion/year in the U.S.A alone, and thus require significant attention. Despite several decades of research, the mechanisms by which the insidious transition from gingivitis to severe forms of PD occurs is poorly understood. Consequently, there has been little progress in biomarker based diagnosis / monitoring of disease activity, as well, as in development of new therapeutic options. PGRP3 are novel secreted and soluble receptors that recognize and respond to bacteria and are emerging as crucial mediators of inflammation. However, their expression and functional role in PD and the associated dysbiosis remains a critical knowledge gap. Therefore, the overall objective of this application is to understand the role of PGRP3 in PD and is based on the scientific premise that, PGRP3 binds to select constituents of the oral microbiome and PGRP3 modulates PD immune responses. Towards that, this proposal aims to test the central hypothesis PGRP3 selectively targets particular species found in dysbiotic PD plaque and PGRP3+ cells in PD gingiva exhibit a distinct transcriptome compared to PGRP3- cells found in the same local environment. The central hypothesis will be tested by pursuing two specific aims: 1) Identify PGRP3-targeted microbiota in PD and health and characterize the immune response to them. & 2) Analyze and compare the transcriptomes of PGRP3+ and PGRP3- immune subsets of PD and healthy gingiva. Under aim 1, bacteria-PGRP3 interactomes will be identified by adapting a novel flow cytometry- based bacterial cell sorting/16S sequencing assay and the immune response to the highly coating species will be studied. For the second aim, we will separate the immune subset that we have identified to be PGRP3+ into PGRP3+ and PGRP- populations through multicolor flow cytometry on gingival single cell suspensions excised from healthy and PD subjects. We will compare the transcriptomes of the PGRP3+ and PGRP- subsets to understand their functional role in the local environmental context. These results will be validated with multiplex immunofluorescence techniques. This research is innovative because it focuses on a never before explored group of molecules in the oral context and it will involve the adaptation and development of novel techniques and strategies. The proposed research would be significant as they are expected to provide strong scientific justification for dissecting the role of PGRP3 in PD dysbiosis and inflammatory dysregulation. Ultimately, such knowledge would offer new therapeutic and diagnostic options for PD and other inflammatory diseases.

项目总结