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Redox Regulation of Gingival Inflammation

牙龈炎症的氧化还原调节

基本信息

批准号：
10579090
负责人：
Juhi Bagaitkar
金额：
$ 36.73万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
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 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10579090
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.

项目摘要