Redox Regulation of Gingival Inflammation

牙龈炎症的氧化还原调节

• 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
• 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

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.

项目摘要摘要 PI：Bagaitkar 牙周疾病是高度常见的传染病。牙周炎的慢性炎症导致 逐渐破坏硬组织和软组织，并增强对其他全身性疾病的敏感性。主人 调节口服炎症反应的大小，性质和持久性的因素是 不完全理解。我们以前已经表明，由 白细胞NADPH氧化酶复合物的激活在衰减高炎症中起着关键作用 回答。小鼠的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分辨率延迟。这些数据支持有些违反直觉 ROS在限制宿主炎症中的作用。氧化剂是否调节口腔中的炎症途径 不清楚。我们的中心假设是NADPH氧化酶衍生的ROS，独立于其抗菌剂 功能，在体外和体内的中性粒细胞和巨噬细胞效应子功能的氧化还原调节中起关键作用。 此外，我们假设虽然过量的ROS与 牙周疾病，低水平的局部ROS反应是免疫调节的。这些假设将是 以两个具体目标进行测试。 1）确定NADPH氧化酶在PMN效应函数调节中的作用 在牙龈中的急性反应中。 2）确定NADPH氧化酶在巨噬细胞调节中的作用 牙龈炎症的功能和分辨率。使用缺乏NADPH氧化酶的有条件敲除小鼠 在中性粒细胞或巨噬细胞中有选择性的活性将使我们能够专门确定氧化剂在 细胞在体内的内在方式。这些研究产生的数据将在我们的 了解与牙龈炎症及其对氧化剂调节相关的免疫途径。更远， 我们的研究也与理解慢性肉芽肿性疾病的免疫病理学相关， 由NADPH氧化酶亚基基因遗传突变引起的威胁生命的免疫缺陷。