PGRP3 is a crucial mediator of periodontitis

PGRP3是牙周炎的重要介质

• 批准号: 10285296
• 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 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10285296
• 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 牙周炎是引起牙槽骨溶解的最常见的慢性感染性疾病之一。 骨质和牙齿脱落。据估计，超过47%的美国成年人口患有某种形式的帕金森病。在……里面 65岁的成年人，这一患病率上升到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有关的财政负担估计为10.5美元 仅在美国就是10亿/年，因此需要高度关注。尽管经过了几十年的研究，但 从牙周炎到严重形式的帕金森病的潜伏转化发生的机制还知之甚少。 因此，在基于生物标记物的疾病活动性诊断/监测方面进展甚微，因为 嗯，就像开发新的治疗方案一样。PGRP3是一种新的分泌型和可溶性受体 识别细菌并对其作出反应，并成为炎症的关键介质。然而，他们的 帕金森病的表达和功能作用以及与之相关的生物失调仍然是一个关键的知识缺口。因此， 本应用程序的总体目标是了解PGRP3在PD中的作用，并基于科学的 前提是，PGRP3结合选择口腔微生物组的成分，并且PGRP3调节PD免疫 回应。为此，这项建议旨在测试中心假设PGRP3选择性地针对特定目标 PD菌斑中发现的物种和PD牙龈中的PGRP3+细胞显示出明显的转录组 到PGRP3--在相同的局部环境中发现的细胞。核心假说将通过追求两个 具体目标：1)确定帕金森病和健康人群中以PGRP3为靶标的微生物区系，并表征免疫反应 敬他们。&2)分析比较PD和Pd的PGRP3+和PGRP3-免疫亚群的转录本 健康的牙龈。在目标1下，细菌-PGRP3相互作用将通过采用一种新的流式细胞术进行鉴定- 基于细菌细胞分选/16S测序和对高包被物种的免疫反应 被研究。对于第二个目的，我们将我们已经确定为PGRP3+的免疫亚集分离为 多色流式细胞术检测切取的牙周单个细胞悬液中的PGRP3+和PGRP-亚群 来自健康受试者和帕金森病患者。我们将比较PGRP3+和PGRP-亚集的转录本 了解它们在当地环境中的职能作用。这些结果将通过多路传输进行验证 免疫荧光技术。这项研究具有创新性，因为它关注的是一种前所未有的探索 口语中的分子群，它将涉及到新技术的适应和发展 和策略。拟议中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在帕金森氏病生物失调和炎症调节失调中的作用的合理性。最终，这样的 这一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。