PGRP3 is a crucial mediator of periodontitis

PGRP3是牙周炎的重要介质

基本信息

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
项目类别：
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

项目摘要

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.

项目概要牙周炎（PD）是最常见的慢性感染性疾病之一，会导致牙槽骨溶解骨质和牙齿损失。据估计，超过 47% 的美国成年人患有某种形式的帕金森病。在 65 岁以上的成年人，该患病率增加至 >70%，是糖尿病患病率的三倍，并且高于动脉粥样硬化或高血压。与 PD 相关的经济负担估计>10.5 美元仅在美国每年就有十亿美元，因此需要高度重视。尽管经过几十年的研究，从牙龈炎到严重帕金森病的隐秘转变的机制尚不清楚。因此，基于生物标志物的疾病活动诊断/监测进展甚微，因为好吧，就像开发新的治疗方案一样。 PGRP3 是新型分泌型可溶性受体识别细菌并对其作出反应，并正在成为炎症的重要介质。然而，他们的 PD 中的表达和功能作用以及相关的生态失调仍然是一个关键的知识空白。所以，该应用的总体目标是了解 PGRP3 在 PD 中的作用，并基于科学依据前提是，PGRP3 与口腔微生物组的选定成分结合，并且 PGRP3 调节 PD 免疫回应。为此，该提案旨在测试中心假设 PGRP3 选择性地针对特定目标与 PD 菌斑和 PD 牙龈中的 PGRP3+ 细胞相比，在生态失调的 PD 斑块中发现的物种表现出不同的转录组到在同一本地环境中发现的 PGRP3- 细胞。中心假设将通过追求两个具体目标：1) 识别 PD 和健康中的 PGRP3 靶向微生物群并表征免疫反应给他们。 & 2) 分析比较PD和PGRP3+和PGRP3-免疫亚群的转录组健康的牙龈。在目标 1 下，将通过采用新型流式细胞术来鉴定细菌-PGRP3 相互作用组。基于细菌细胞分选/16S测序测定和对高度包被物种的免疫反应将被研究。对于第二个目标，我们将我们已识别为 PGRP3+ 的免疫子集分离为通过多色流式细胞术对切除的牙龈单细胞悬液进行 PGRP3+ 和 PGRP- 群体分析来自健康和帕金森病受试者。我们将比较 PGRP3+ 和 PGRP- 子集的转录组了解它们在当地环境中的功能作用。这些结果将通过多重验证免疫荧光技术。这项研究具有创新性，因为它关注的是以前从未探索过的口腔环境中的分子群，它将涉及新技术的适应和发展和策略。拟议的研究将具有重要意义，因为它们有望提供强有力的科学依据剖析 PGRP3 在 PD 生态失调和炎症失调中的作用的理由。最终，这样的这些知识将为帕金森病和其他炎症性疾病提供新的治疗和诊断选择。