Functional role of serum amyloid A in periapical inflammation (R01 Renew)

血清淀粉样蛋白 A 在根尖周炎症中的功能作用 (R01 Renew)

• 批准号: 10667247
• 负责人: HAJIME SASAKI
• 金额: $ 40.2万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10667247
• 关键词: Adipose tissue; Adult; Antibody Response; Antigen-Antibody Complex; Antigens; Apoptotic; Autoimmunity; B-Lymphocytes; Body fat; C57BL/6 Mouse; Cells; Chemotaxis Induction; Chromosomes; Chronic; Complement; Complement Activation; Complement Inactivators; Complex; Data; Dental; Development; Disease; Disease susceptibility; Endodontics; Environment; Fatty Liver; Frequencies; Gene Expression Profile; Genes; Goals; Granulomatous; Health; High Fat Diet; Human; IgG1; Immune; Immunoglobulin G; Immunoglobulin M; Immunoglobulins; Infection; Inflammation; Injury; Kinetics; Knowledge; Lesion; Life; Link; Liver; Mission; Molecular; Mus; NF-kappa B; Obesity; Oral; Osteitis; Outcome; Overweight; Oxides; Passive Transfer of Immunity; Pathogenesis; Pathogenicity; Pathologic; Pattern; Periapical Periodontitis; Plant Roots; Play; Property; Public Health; Reporting; Resistance; Role; Serum amyloid A protein; Structure; Testing; Thinness; Time; Tissues; United States National Center for Health Statistics; United States National Institutes of Health; Weight Gain; Wild Type Mouse; X Chromosome; adaptive immunity; antibody transfer; bone; burden of illness; conventional therapy; cytokine; dental infection; diet-induced obesity; dietary control; disability; disease phenotype; experience; gene complementation; global health; immunoregulation; innovation; macrophage; microorganism; natural antibodies; neoantigens; neutrophil; novel; novel therapeutics; obese person; obesity development; obesity risk; pathogen; periapical; success; tissue injury; transcriptome sequencing

Project Summary/Abstract The long-term goal of our serum amyloid A (SAA) project is to determine the cellular/molecular networks that regulate the development of infection-induced dental inflammation/bone destruction in the over body fat status. This renewal application seeks to test a new pathological paradigm that SAA is responsible for obesity and its associated inflammations via altering the natural antibody (NAb) profile in a high-fat diet (HFD) environment. Obesity is a global health concern. Obesity exacerbates periapical periodontitis (periapical lesions), leading to a poor success rate of treatment. Yet, understanding of the detailed pathogenesis of periapical lesions in obese hosts is still insufficient. SAA is inducible in such as the liver, adipose tissue, and macrophages caused by inflammation including periapical lesions and obesity. NAb are heterogenous immunoglobulins secreted by B-1 B cells in the absence of prior antigenic experience (e.g. infection). NAb provides immediate and non-specific protection against infection during the establishment of adaptive immunity over some time period. Also, NAb is important in the clearance of damaged/apoptotic cells. In opposite, antigens complexed with NAb (immune com- plexes) may cause tissue injury via complement activation and neutrophil-dependent inflammation. We have reported that, under normal body fat status, SAA plays a cytokine-like role in the induction of chemo- taxis, activation of the TLR-NF-kB axis in the development of chronic periapical inflammation, but not in bone destruction. Next, we examined the role of SAA in periapical lesions in HFD-induced obesity. Obese wild-type (WT) mice gained >75% larger lesion size vs. lean controls. By contrast, HFD-fed SAA-blocked mice were re- sistant to both obesity and periapical inflammation, resulted in no body weight gain and almost no periapical lesions. Significant differences were observed in the gene expression profile of complement and immunoglobulin variable genes. Non-infected obese-WT mice had a NAb profile characterized by a high titer of IgG1 reactive with human endodontic pathogens, while HFD-fed SAA-blocked mice showed a high titer of natural polyreactive IgM. SAA probably plays a hitherto unknown HFD-dependent role in natural antibody response. As complement genes were locally expressed in obese-WT lesions, SAA may bring causal factors for IgG immune complex injury only to WT mice in a HFD environment. Taken together, the overarching hypothesis is that SAA plays a unique HFD-dependent pathologic role in promotion of periapical inflammation and obesity via changing of NAb profile. We will test the hypothesis through the following Specific Aims. Aim 1. To examine the effect of SAA on the role of NAb in a HFD environment. Aim 2. To examine whether SAA leads to IgG immune complex periapical injury in a HFD environment. Aim 3. To determine the effect of passive NAb transfer on the disease development. The outcome of this project will lead to a paradigm shift in the pathogenesis of periapical lesions in obesity and a new therapeutic paradigm in a different manner of conventional therapies.

项目总结/文摘

项目成果

Hypochlorous acid inactivates oral pathogens and a SARS-CoV-2-surrogate.

• DOI: 10.1186/s12903-023-02820-7
• 发表时间: 2023-02-18
• 期刊: BMC ORAL HEALTH
• 影响因子: 2.9
• 作者: Tazawa, Kento;Jadhav, Rutuja;Azuma, Mariane Maffei;Fenno, J. Christopher;McDonald, Neville J.;Sasaki, Hajime
• 通讯作者: Sasaki, Hajime