Redox Regulation of Gingival Inflammation

牙龈炎症的氧化还原调节

基本信息

批准号：
10308384
负责人：
Juhi Bagaitkar
金额：
$ 9.05万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-09 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10308384
关键词：
Acute Alleles Alveolar Bone Loss Autoimmune Diseases Cells Chronic Chronic Granulomatous Disease Clinical Research Communicable Diseases Complex Data Diffusion Disease Effector Cell Enzymes Etiology Family Functional disorder Generations Genes Genetic Genetic Transcription Gingiva Immune Immune response Immunologic Deficiency Syndromes In Vitro Inflammation Inflammatory Inflammatory Response Inherited Integration Host Factors Knockout Mice Leukocytes Life Ligature Literature Mediating Multienzyme Complexes Mus Mutation NADPH Oxidase Nature Oral Oral cavity Oral mucous membrane structure Outcome Oxidants Oxidases Oxidation-Reduction Oxygen Pathogenesis Pathway interactions Periodontal Diseases Periodontitis Play Predisposition Production Publishing Reactive Oxygen Species Regulation Resolution Risk Role Source Superoxides Systemic disease Testing Tissues Tooth structure Work antimicrobial base conditional knockout cytokine dysbiosis immunopathology immunoregulation in vivo inhibitor insight leukocyte activation macrophage neutrophil novel oral microbiome recruit response soft tissue

项目摘要

Project Summary Abstract PI: Bagaitkar Periodontal diseases are highly common infectious diseases. Chronic inflammation in periodontitis results in the progressive destruction of hard and soft tissues and enhances susceptibility to other systemic disease. The host factors that regulate the magnitude, nature and persistence of inflammatory responses in the oral are incompletely understood. We have previously shown that reactive oxygen species (ROS) generated by the activation of leukocyte NADPH oxidase enzyme complex plays a critical role in dampening hyperinflammatory responses. Oxidase deficiency in mice resulted in profound inflammation characterized by dysregulated neutrophil and macrophages responses and resolution delays. These data support a somewhat counterintuitive role for ROS in limiting host inflammation. Whether oxidants modulate inflammatory pathways in the oral cavity is unclear. Our central hypothesis is that the NADPH oxidase derived-ROS, independent of their antimicrobial functions, play key roles in redox modulation of neutrophil and macrophage effector functions in vitro and in vivo. Further, we hypothesize that while excessive amounts of ROS are associated with the pathophysiology of periodontal diseases, low-level, localized ROS responses are immuno-regulatory. These hypotheses will be tested in two specific aims. 1) Determine the role of NADPH oxidase in the regulation of PMN effector functions in acute responses in the gingiva. 2) Determine the role of NADPH oxidase in the modulation of macrophage function and resolution of gingival inflammation. The use of conditional knockout mice that lack NADPH oxidase activity selectively in neutrophils or macrophages will enable us to specifically determine the role of oxidants in a cell intrinsic manner in vivo. The data generated by these studies will shed key mechanistic insights in our understanding of immune pathways relevant in gingival inflammation and their regulation by oxidants. Further, our studies are also highly relevant in understanding the immunopathology of chronic granulomatous disease, a life-threatening immunodeficiency caused by inherited mutations in NADPH oxidase subunit genes.

项目概要摘要 PI：巴盖特卡牙周病是非常常见的感染性疾病。牙周炎的慢性炎症会导致硬组织和软组织的逐渐破坏并增加对其他全身性疾病的易感性。主人调节口腔炎症反应的程度、性质和持续时间的因素是不完全理解。我们之前已经表明，由白细胞 NADPH 氧化酶复合物的激活在抑制过度炎症中发挥着关键作用回应。小鼠氧化酶缺乏导致严重的炎症，其特征是失调中性粒细胞和巨噬细胞的反应和解决延迟。这些数据支持了一个有点违反直觉的观点 ROS 在限制宿主炎症中的作用。氧化剂是否调节口腔炎症途径尚不清楚。我们的中心假设是 NADPH 氧化酶衍生的 ROS，与其抗菌作用无关功能，在体外和体内中性粒细胞和巨噬细胞效应功能的氧化还原调节中发挥关键作用。此外，我们假设过量的 ROS 与以下疾病的病理生理学有关：牙周疾病中，低水平的局部 ROS 反应具有免疫调节作用。这些假设将在两个特定目标上进行了测试。 1）确定NADPH氧化酶在PMN效应功能调节中的作用牙龈的急性反应。 2）确定NADPH氧化酶在巨噬细胞调节中的作用牙龈炎症的功能和解决。使用缺乏NADPH氧化酶的条件敲除小鼠中性粒细胞或巨噬细胞中选择性的活性将使我们能够具体确定氧化剂在体内细胞固有的方式。这些研究产生的数据将为我们提供关键的机制见解了解与牙龈炎症相关的免疫途径及其受氧化剂的调节。更远，我们的研究对于了解慢性肉芽肿病的免疫病理学也高度相关，这是一种由 NADPH 氧化酶亚基基因遗传突变引起的危及生命的免疫缺陷。