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.

项目摘要 牙周炎（PD）是最普遍的慢性传染病之一，导致肺泡的溶解性 骨骼和牙齿脱落。据估计，超过47％的美国成年人人口具有某种形式的PD。在 成人> 65，这种流行率增加到> 70％，是糖尿病患病率的三倍，高于 动脉粥样硬化或高血压。与PD相关的财务负担估计为10.5美元 仅在美国，就需要十亿美元，因此需要大大关注。尽管进行了数十年的研究，但 从牙龈炎到严重形式的PD发生的阴险过渡的机制知之甚少。 因此，基于生物标志物的疾病活动的诊断 /监测几乎没有进展， 好吧，就像开发新的治疗选择一样。 pgrp3是新颖的分泌和可溶的受体 识别并应对细菌，并成为炎症的关键介质。但是，他们 在PD和相关的营养不良中的表达和功能作用仍然是一个关键的知识差距。所以， 该应用的总体目的是了解pgrp3在PD中的作用，并基于科学 pgrp3与选择口服微生物组的成分和pgrp3调节PD免疫的前提 回答。在此方面，该提案旨在测试中央假设pgrp3特定目标 在PD牙龈中发现的生物PD斑块和pgrp3+细胞中发现的物种表现出独特的转录组。 到在同一局部环境中发现的pgrp3细胞。中心假设将通过追求两个来检验 具体目的：1）在PD和健康中识别pgrp3靶向的微生物群，并表征免疫反应 给他们。 ＆2）分析和比较pgrp3+和pgrp3-免疫子集的转录组和 健康的牙龈。在AIM 1下，将通过适应新的流式细胞术来鉴定细菌-PGRP3相互作用。 基于细菌细胞分选/16S测序测定法和对高度涂层物种的免疫反应将 被研究。为了第二个目标，我们将把我们已确定为pgrp3+的免疫子集中 pgrp3+和PGRP种群通过牙龈单细胞悬浮液上的多色流式细胞仪切除 来自健康和PD受试者。我们将将pgrp3+和pgrp-子集的转录组与 了解他们在当地环境环境中的功能作用。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，因为它专注于前所未有的探索 在口服环境中的一组分子，它将涉及新技术的适应和发展 和策略。拟议的研究将非常重要，因为他们预计将提供强大的科学 剖析pgrp3在PD营养不良和炎症失调中的作用的理由。最终，这样的 知识将为PD和其他炎症性疾病提供新的治疗和诊断选择。