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）是最常见的慢性感染性疾病之一，可导致牙槽骨溶解 骨质和牙齿脱落。据估计，超过47%的美国成年人患有某种形式的PD。在 对于>65岁的成年人，这种患病率增加到> 70%，是糖尿病患病率的三倍， 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 仅在美国就有10亿美元/年，因此需要引起极大的关注。尽管经过几十年的研究， 从牙龈炎到严重形式的PD的潜伏转变发生的机制知之甚少。 因此，在基于生物标志物的疾病活动的诊断/监测方面几乎没有进展， 比如开发新的治疗方案PGRP 3是新型分泌性和可溶性受体， 识别并对细菌作出反应，并成为炎症的重要介质。但他们的 在PD和相关的生态失调中的表达和功能作用仍然是一个关键的知识差距。因此，我们认为， 本申请的总体目标是了解PGRP 3在PD中的作用， 前提是，PGRP 3与口腔微生物组的选择成分结合，并且PGRP 3调节PD免疫 应答为此，该提议旨在测试PGRP 3选择性靶向特定的核心假设。 在PD菌斑中发现的微生物和PD牙龈中的PGRP 3+细胞表现出不同的转录组， PGRP 3-细胞在相同的局部环境中发现。中心假设将通过追求两个来检验 具体目标：1）鉴定PD和健康中的PGRP 3靶向微生物群，并表征免疫应答 给他们.和2）分析和比较PD的PGRP 3+和PGRP 3-免疫亚群的转录组， 健康的牙龈根据目标1，将通过采用新的流式细胞术来鉴定细菌-PGRP 3相互作用组- 基于细菌细胞分选/16 S测序测定和对高度包被物种的免疫应答将 被研究。对于第二个目标，我们将把我们已识别为PGRP 3+的免疫子集分离为 PGRP 3+和PGRP-群体，通过流式细胞术对牙龈单细胞悬液进行切除 来自健康和PD受试者。我们将比较PGRP 3+和PGRP-亚群的转录组， 了解其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。这项研究是创新的，因为它关注的是一个从未探索过的领域。 口腔环境中的一组分子，它将涉及新技术的适应和发展 和战略。拟议的研究将是重要的，因为他们预计将提供强有力的科学 分析PGRP 3在PD生态失调和炎症失调中的作用的理由。最终，这样的 知识将为PD和其他炎性疾病提供新的治疗和诊断选择。