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) 分析和比较PD和PGRP3+和PGRP3-免疫子集的转录组 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浮液进行 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。