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

项目摘要/摘要 我们血清淀粉样蛋白A(SAA)项目的长期目标是确定 调节体内过度脂肪状态下感染引起的牙科炎症/骨破坏的发展。 这一更新应用程序试图测试一种新的病理范式，即SAA对肥胖负有责任，其 通过改变高脂饮食(HFD)环境中的天然抗体(NAB)特征而导致的相关炎症。 肥胖是一个全球性的健康问题。肥胖加剧了根尖周炎(根尖周围病变)，导致 治疗成功率低。然而，对肥胖者根尖周病变的详细发病机制的了解 主机数量仍然不足。SAA在肝脏、脂肪组织和巨噬细胞中是可诱导的，由 炎症包括根尖周围病变和肥胖。NAB是由B-1分泌的异源免疫球蛋白 B细胞，以前没有抗原性经验(例如感染)。NAB提供即时和非特定 在建立一段时间的适应性免疫期间防止感染。此外，NAB是 在清除受损/凋亡细胞方面很重要。相反，抗原与NAB(免疫球蛋白)络合。 神经丛)可能通过补体激活和中性粒细胞依赖的炎症引起组织损伤。 我们已经报道，在正常体脂状态下，SAA在诱导化疗中发挥细胞因子样作用。 趋向性，TLR-NF-kB轴的激活在慢性根尖周炎的发展中的作用，而不是在骨骼中 毁灭。接下来，我们研究了SAA在高脂诱导肥胖的根尖周围病变中的作用。肥胖野生型 与瘦对照组相比，(WT)小鼠的病变面积增加了75%。相比之下，高脂饲料喂养的SAA被阻断的小鼠 同时抵抗肥胖和根尖周炎，导致体重没有增加，几乎没有根尖周围 损伤。补体和免疫球蛋白的基因表达谱有显著差异 可变基因。未感染的肥胖-WT小鼠的NAB谱特征是高滴度的IgG1反应 用人类牙髓病原体，而HFD喂养的SAA阻断的小鼠显示出高滴度的自然多反应 免疫球蛋白。SAA可能在天然抗体应答中发挥着迄今未知的HFD依赖性作用。作为补语 肥胖WT皮损局部基因表达SAA可能带来免疫复合物损伤的致病因素 仅对HFD环境中的WT小鼠。综上所述，最重要的假设是SAA发挥着独特的 高脂依赖的病理改变在促进根尖周炎和肥胖中的作用。 我们将通过以下具体目标来检验这一假设。 目的1.研究SAA在HFD环境中对NAB作用的影响。 目的2.在HFD环境中检测SAA是否导致免疫球蛋白G免疫复合体的根尖周损伤。 目的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症患者根尖周围病变发病机制的范式转变。 一种新的治疗模式，与传统治疗方法不同。

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.