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.

项目摘要/摘要 我们的血清淀粉样蛋白A（SAA）项目的长期目标是确定细胞/分子网络 调节感染引起的牙齿炎症/骨骼破坏的发育。 该更新应用程序旨在测试SAA负责肥胖及其其肥胖症的新病理范式 通过在高脂饮食（HFD）环境中改变天然抗体（NAB）谱的相关炎症。 肥胖是全球健康问题。肥胖症加剧根尖牙周炎（根尖性病变），导致 成功率差。然而，了解肥胖中根尖病变的详细发病机理 主机仍然不足。 SAA在肝脏，脂肪组织和由 炎症，包括根尖的病变和肥胖。 NAB是B-1分泌的异质免疫球蛋白 B细胞在没有先验的抗原经验（例如感染）的情况下。 NAB提供直接和非特异性 在建立自适应免疫期间，防止感染的保护。另外，nab是 对于清除受损/凋亡细胞的清除很重要。相反，抗原与NAB复合 丛）可能会通过补体激活和中性粒细胞依赖性炎症引起组织损伤。 我们报告说，在正常的体内脂肪状态下，SAA在化学诱导中起细胞因子样作用 出租车，在慢性根尖炎症的发展中激活TLR-NF-KB轴，但在骨骼中却没有 破坏。接下来，我们检查了SAA在HFD诱导的肥胖症中的根尖性病变中的作用。肥胖的野生型 （wt）较大的病变尺寸与瘦门控制的小鼠获得了> 75％。相比之下，HFD喂养的SAA封锁小鼠是重新的 肥胖和根尖炎症都伴有体重增加，几乎没有根尖 病变。在补体和免疫球蛋白的基因表达谱中观察到显着差异 可变基因。未感染的肥胖-WT小鼠的NAB谱为具有IgG1反应性的高滴度为特征 使用人类牙髓病原体，而HFD喂养的SAA受体障碍小鼠表现出很高的天然多反应性 Igm。 SAA可能在天然抗体反应中迄今曾在HFD依赖性依赖性作用中扮演。作为补充 基因在肥胖的WT病变中局部表达，SAA可能带来IgG免疫复合损伤的因子 仅用于HFD环境中的WT小鼠。综上所述，总体假设是SAA扮演着独特的 HFD依赖性的病理作用在促进根尖的炎症和肥胖中，通过改变NAB谱。 我们将通过以下特定目标检验假设。 目的1。检查SAA对NAB在HFD环境中的作用的影响。 目的2。检查SAA是否导致HFD环境中IgG免疫复合物细胞损伤。 目标3。确定被动NAB转移对疾病发展的影响。 该项目的结果将导致肥胖和肥胖细胞病变发病机理的范式转移 一种新的治疗范式，采用不同方式的常规疗法。

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